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  • 101.
    Andappan, Murugaiah M S
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    Larhed, Mats
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    The first ligand-modulated oxidative Heck vinylation. Efficient catalysis with molecular oxygen as palladium(0) oxidant.2004Ingår i: Chem Commun (Camb), ISSN 1359-7345, nr 2, s. 218-9Artikel i tidskrift (Övrigt vetenskapligt)
  • 102.
    Andappan, Murugaiah M S
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    von Schenck, Henrik
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    Larhed, Mats
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. OrgFarmKemi.
    Dioxygen-promoted regioselective oxidative heck arylations of electron-rich olefins with arylboronic acids.2004Ingår i: J Org Chem, ISSN 0022-3263, Vol. 69, nr 16, s. 5212-8Artikel i tidskrift (Refereegranskat)
  • 103.
    Andappan, Murugaiah M. S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wu, Xiongyu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wallinder, Charlotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Mahalingam, A. K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wan, Yiqian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Botros, Milad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Guimond, Marie-Odile
    Joshi, Advait
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gallo-Payet, Nicole
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Alterman, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists2012Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 5, s. 2265-2278Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K-i ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells.. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.

  • 104.
    Andappan, Murugaiah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nilsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Arylboronic acids as versatile coupling partners in fast microwave promoted oxidative Heck chemistry2003Ingår i: Molecular diversity, ISSN 1381-1991, E-ISSN 1573-501X, Vol. 7, nr 2-4, s. 97-106Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The useful and selective reactivity of arylboronic acids makes them favourite building blocks for many modern organic chemistry applications like the metal-mediated formation of C-C, C-O, C-N, and C-S bonds. This report describes oxidative Heck coupling reactions of arylboronic acids and olefins, which were conveniently and rapidly (5-30 min) carried out under air with temperature-controlled microwave heating. Different reaction conditions were investigated with regard to both microwave heating capability and chemical productivity. Copper(II) acetate was identified as a microwave compatible reoxidant of Pd(0). The scope and limitations of this high-speed chemistry protocol with diverse olefins and organoboronic acids are discussed.

  • 105. Andersen, Thomas L.
    et al.
    Friis, Stig D.
    Audrain, Helene
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Skrydstrup, Troels
    Efficient C-11-Carbonylation of Isolated Aryl Palladium Complexes for PET: Application to Challenging Radiopharmaceutical Synthesis2015Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, nr 4, s. 1548-1555Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe the successful implementation of palladium-aryl oxidative addition complexes as stoichiometric reagents in carbonylation reactions with (CO)-C-11 to produce structurally challenging, pharmaceutically relevant compounds. This method enables the first C-11-carbonyl labeling of an approved PET tracer, [C-11]raclopride, for the dopamine D2/D3 receptor by carbonylation with excellent radiochemical purity and yield. Two other molecules, [C-11]olaparib and [C-11]JNJ 31020028, were efficiently labeled in this manner. The technique distinguishes itself from existing methods by the markedly improved purity profiles of the tracer molecules produced and provides access to complex structures in synthetically useful yields, hereby offering a viable alternative to other C-11-labeling strategies.

  • 106.
    Andersen, Thomas L.
    et al.
    Aarhus Univ, Carbon Dioxide Activat Ctr CADIAC, Dept Chem, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark..
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Christoffersen, Heidi F.
    Aarhus Univ, Carbon Dioxide Activat Ctr CADIAC, Dept Chem, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark..
    Audrain, Helene
    Aarhus Univ Hosp, Dept Nucl Med, DK-8000 Aarhus, Denmark.;Aarhus Univ Hosp, PET Ctr, DK-8000 Aarhus, Denmark..
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Skrydstrup, Troels
    Aarhus Univ, Carbon Dioxide Activat Ctr CADIAC, Dept Chem, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark..
    Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-C-11-Acetylation of Peptides2017Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 56, nr 16, s. 4549-4553Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A mild and effective method is described for C-11-labeling of peptides selectively at the N-terminal nitrogen or at internal lysine positions. The presented method relies on the use of specific biphosphine palladium-methyl complexes and their high reactivity towards amino-carbonylation of amine groups in the presence [C-11] carbon monoxide. The protocol facilitates the production of native N-C-11-acetylated peptides, without any structural modifications and has been applied to a selection of bioactive peptides.

  • 107. Andersson, CM
    et al.
    Hallberg, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hogberg, T
    Advances in the development of pharmaceutical antioxidants1996Ingår i: Advances in Drug Research, Vol. 28, s. 65-Artikel i tidskrift (Refereegranskat)
  • 108.
    Andersson Dunstan, Christina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Liu, Boling
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Welch, Christopher J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Alphitol, a phenolic substance from Alphitonia zizyphoides which inhibits prostaglandin biosynthesis in vitro1998Ingår i: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 48, nr 3, s. 495-497Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The new phenolic compound, 3,5-dihydroxy-4-methoxy phenethyl alcohol, named alphitol, and betulinic acid were isolated from the bark of Alphitonia zizyphoides. The chemical structure of alphitol was determined by mass spectrometry in combination with one and two dimensional NMR, including HMBC. Both compounds inhibited prostaglandin biosynthesis in vitro, alphitol with an IC50 value of 0.66 mM, which is of the same magnitude as acetyl salicylic acid.

  • 109.
    Andersson Dunstan, Christina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Noreen, Ylva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Serrano, Gudelia
    Cox, Paul A
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Evaluation of some Samoan and Peruvian medicinal plants by prostaglandin biosynthesis and rat ear oedema assays1997Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 57, nr 1, s. 35-56Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In our ongoing program to find new anti-inflammatory compounds, 58 extracts from 46 different medicinal plant species, used in treatment of inflammatory disorders - 38 plants from the traditional medicine of Western Samoa and eight originating from the indigenous medicine of the Shipibo-Conibo tribe of Peruvian Amazonia - were evaluated. The ability of all extracts to inhibit cyclooxygenase-1 catalysed prostaglandin biosynthesis in vitro was examined. Of the plant species tested 14 showed moderate to strong inhibition; including 11 Samoan and three Peruvian species. Further, 12 Samoan and all eight Peruvian species were investigated on their inhibitory activity of ethyl phenylpropiolate induced rat ear oedema in vivo Significant activity was shown by 10 of the Samoan and by all eight Peruvian species. An additional evaluation of the most active species was provided through a compilation of existing literature documenting traditional medicinal uses, pharmacological activity and chemical constituents. Several known cyclooxygenase-l inhibitors were reported to which the observed pharmacological activity can be attributed at least partly. The combination of chemical and pharmacological literature data and our experimental data may help to explain the anti-inflammatory use of these species in indigenous medicine.

  • 110.
    Andersson, H. S.
    et al.
    Linnaeus Univ, Ctr Biomat Chem, Dept Chem & Biomed Sci, Norra Vagen 49, S-39234 Kalmar, Sweden..
    Jacobsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Eriksson, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Hedstrom, M.
    Lund Univ, Dept Biotechnol, Box 118, S-22100 Lund, Sweden..
    Seth, H.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden..
    Sundberg, P.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden..
    Rosengren, K. J.
    Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia..
    Strand, M.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden.;Swedish Univ Agr Sci, Swedish Species Informat Ctr, Backlosavagen 10, S-75651 Uppsala, Sweden..
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    The toxicity of ribbon worms: Alpha-nemertides or tetrodotoxin, or both?2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 111.
    Andersson, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Peptidomimetics derived from the bioactive hexapeptide angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) have been designed and synthesized. These peptidomimetics are aimed at inhibiting the insulin-regulated amino peptidase (IRAP), also known as the AT4 receptor. This membrane-bound zinc-metallopeptidase is currently under investigation regarding its potential as a target for cognitive enhancers. The work presented herein was based on stepwise replacement of the amino acid residues in Ang IV by natural and unnatural amino acids, non-peptidic building blocks, and also on the introduction of conformational constraints. Initially, we focused on the introduction of secondary structure mimetics and backbone mimetics. The C-terminal tripeptide His-Pro-Phe was successfully replaced by a γ-turn mimetic scaffold, 2-(aminomethyl)phenylacetic acid (AMPA), which was coupled via an amide bond to the carboxyl terminus of Val-Tyr-Ile. Substitution of Val-Tyr-Ile, Val-Tyr, Tyr-Ile and Tyr, respectively, by 4-hydroxydiphenylmethane scaffolds comprising a 1,3,5-substituted benzene ring as a central moiety unfortunately rendered peptidomimetics that were less potent than Ang IV. The subsequent approach involved the introduction of conformational constraints into Val-Tyr-Ile-AMPA by replacing Val and Ile by amino acid residues appropriate for disulfide cyclization or ring-closing metathesis. Chemically diverse structures encompassing an N-terminal 13- or 14-membered macrocyclic tripeptide and a C-terminal non-peptidic moiety were developed. Tyr2 and AMPA were modified to acquire further knowledge about the structure-activity relationships and, in addition, to improve the metabolic stability and reduce the polarity. Several of the compounds displayed a high capacity to inhibit IRAP and exhibited Ki values in the low nanomolar range. Hence, the new compounds were more than ten times more potent than the parent peptide Ang IV. Enhanced selectivity over the closely related aminopeptidase N (AP-N) was achieved, as well as improved stability against proteolysis by metallopeptidases present in the assays. However, additional investigations are required to elucidate the bioactive conformation(s) of the relatively flexible N-terminal macrocycles. The compounds presented in this thesis have provided important information on structure-activity relationships regarding the interaction of Ang IV-related pseudopeptides and peptidomimetics with IRAP. The best compounds in the series constitute important starting points for further discovery of Ang IV peptidomimetics suitable as tools in the investigation of IRAP and other potential targets for Ang IV. The literature presents strong support for the hypothesis that drug-like IRAP inhibitors would serve as a new type of future cognitive enhancers with potential use in the treatment of cognitive disorders, e.g. Alzheimer’s disease.

    Delarbeten
    1. Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
    Öppna denna publikation i ny flik eller fönster >>Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
    Visa övriga...
    2007 (Engelska)Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, nr 7, s. 434-444Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.

    Nyckelord
    Adult neural stem cells, Angiotensin IV, Bioactive conformation, Insulin-regulated aminopeptidase, IRAP, Peptide synthesis, Peptidemimetic, Structure-activity relationship, Turn mimetic
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-16622 (URN)10.1002/psc.859 (DOI)000248164400002 ()17559064 (PubMedID)
    Tillgänglig från: 2008-05-29 Skapad: 2008-05-29 Senast uppdaterad: 2018-03-20Bibliografiskt granskad
    2. Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
    Öppna denna publikation i ny flik eller fönster >>Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
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    2008 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, nr 14, s. 6924-6935Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

    Nyckelord
    Angiotensin IV, Insulin-regulated aminopeptidase (IRAP), Cystinyl aminopeptidase (CAP), Aminopeptidase N (AP-N), Structure–activity relationship, Peptide synthesis, Peptide mimetic, 4-Hydroxydiphenylmethane, Tyrosine mimetic
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-102954 (URN)10.1016/j.bmc.2008.05.046 (DOI)000257829600031 ()18556208 (PubMedID)
    Tillgänglig från: 2009-05-13 Skapad: 2009-05-13 Senast uppdaterad: 2018-03-20Bibliografiskt granskad
    3. Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
    Öppna denna publikation i ny flik eller fönster >>Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
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    2010 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 22, s. 8059-8071Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

    Nyckelord
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, disulfide, NAMFIS
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-122213 (URN)10.1021/jm100793t (DOI)000284287200016 ()21047126 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2018-03-20Bibliografiskt granskad
    4. Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
    Öppna denna publikation i ny flik eller fönster >>Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
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    2011 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 11, s. 3779-3792Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

    Nyckelord
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, macrocyclic, ring-closing metathesis
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-122208 (URN)10.1021/jm200036n (DOI)000291082500008 ()21476495 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2018-05-29Bibliografiskt granskad
  • 112.
    Andersson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Johnsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Erdélyi, Máté
    Department of Chemistry, University of Gothenburg.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis2011Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 11, s. 3779-3792Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

  • 113.
    Andersson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Demaegdt, Heidi
    Vauquelin, Georges
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr22008Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, nr 14, s. 6924-6935Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

  • 114.
    Andersson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Erdélyi, Máté
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)2010Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 22, s. 8059-8071Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

  • 115.
    Andersson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers2012Ingår i: International Journal of Hypertension, ISSN 2090-0384, Vol. 2012, s. 789671-Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.

  • 116.
    Andersson, Hans O.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Fridborg, Kerstin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Löwgren, Seved
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Alterman, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Mühlman, Anna
    Björsne, Magnus
    Garg, Neeraj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Kvarnström, Ingemar
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Classon, Björn
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Ahlsén, Göran
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Nillroth, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Vrang, Lotta
    Öberg, Bo
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors2003Ingår i: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, nr 8, s. 1746-1758Artikel i tidskrift (Refereegranskat)
  • 117.
    Andersson, Inger
    et al.
    Department of Molecular Biology, Swedish University of Agricultural Sciences.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Structure and function of Rubisco2008Ingår i: Plant physiology and biochemistry (Paris), ISSN 0981-9428, E-ISSN 1873-2690, Vol. 46, nr 3, s. 275-291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is the major enzyme assimilating CO2 into the biosphere. At the same time Rubisco is an extremely inefficient catalyst and its carboxylase activity is compromised by an opposing oxygenase activity involving atmospheric O2. The shortcomings of Rubisco have implications for crop yield, nitrogen and water usage, and for the global carbon cycle. Numerous high-resolution crystal structures of different forms of Rubisco are now available, including structures of mutant enzymes. This review uses the information provided in these structures in a structure-based sequence alignment and discusses Rubisco function in the context of structural variations at all levels – amino acid sequence, fold, tertiary and quaternary structure – with an evolutionary perspective and an emphasis on the structural features of the enzyme that may determine its function as a carboxylase.

  • 118.
    Andersson, Jennie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Asplund, Veronika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Yavari, Nazila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    In Vitro Therapy Modeling of HER2 Targeting Therapy in Disseminated Prostate Cancer2014Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 45, nr 5, s. 2153-2158Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prostate cancer (PCa) is the most common cancer type among men. Treatments against advanced PCa are limited and in many cases only palliative. In a later, androgent independent, stage of PCa androgen receptors can be activated without interaction with ligand, i.e., by receptors of tyrosine kinase (RTK) family in the outlaw pathway. Human epidermal growth factor receptors HER2 and EGFR belong to RTK-family. HER2 is one of the main actors in the outlaw pathway with EGFR as the preferable heterodimerizing partner. We hypothesized that information on HER2 expression in advanced PCa could be useful for selection of patients for anti-RTK therapy and monitoring of therapy response. A panel of PCa cell lines (LNCap, PC3, DU-145) was subjected to a 8-week treatment using drugs influencing the RTK: trastuzumab (anti‑HER2), 17-DMAG (Hsp90 inhibitor), alone or in combination, and their HER2 and EGFR expressions were compared with non-treated cells. Treatment with trastuzumab decreased proliferation of LNCap and DU-145 cell lines, while 17-DMAG and trastuzumab/17‑DMAG combination affected all three cell lines. HER2 expression was significantly increased in PC3 cells, the most resistant cell line. On the contrary, in responding cells (LNCap and DU-145) HER2 expression decreased, accompanied by increased EGFR expression. However, additional treatment of cells with cetuximab (anti‑EGFR) did not give any additive effect to trastuzumab. In this study the response to anti-RTK therapy proved to vary between different PCa cell lines. We have demonstrated that RTK targeting treatments may affect the phenotypic profile of PCa tumor cells that correlates with therapy outcome. Observation of such changes during treatment could be used for monitoring and an improved therapy outcome.

  • 119.
    Andersson, Jennie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Imaging of HER2 may improve the outcome of external irradiation therapy for prostate cancer patients2015Ingår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 9, nr 2, s. 950-954Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prostate cancer (PCa) is the most common type of cancer among males. Human epidermal growth factor receptor type 2 (HER2) expression in PCa has been reported by several studies and its involvement in the progression towards androgen-independent PCa has been discussed. External irradiation is one of the existing therapies, which has been demonstrated to be efficient in combination with androgen deprivation therapy for the treatment of advanced PCa. However, 20-40% of patients develop recurrent and more aggressive PCa within 10 years. The current study investigates the involvement of HER2 in survival and radioresistance in PCa cells and we hypothesized that, by monitoring HER2 expression, treatment may be personalized. The PCa cell lines, LNCap, PC3 and DU-145, received a 6 Gy single dose of external irradiation. The number of PC3 cells was not affected by a single dose of radiation, whereas a 5-fold decrease in cell number was detected in LNCap (P<0.00001) and DU-145 (P<0.0001) cells. The HER2 expression in PC3 exhibited a significant increase post irradiation, however, the expression was stable in the remaining cell lines. The administration of trastuzumab post-irradiation resulted in a 2-fold decrease in the PC3 cell number, while the drug did not demonstrate additional effects in LNCap and DU-145 cells, when compared with that of irradiation treatment alone. The results of the present study demonstrated that an increase in membranous HER2 expression in response to external irradiation may indicate cell radioresistance. Furthermore, imaging of HER2 expression prior to and following external irradiation may present a step towards personalized therapy in PCa.

  • 120. Andersson, K. G.
    et al.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Malm, M.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för medicinsk strålfysik.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Lofblom, J.
    Stahl, S.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    111In-labeled NOTA-conjugated Affibody molecules for visualization of HER3 expression in malignant tumors2014Ingår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, nr S2, s. S311-S311, artikel-id OP681Artikel i tidskrift (Övrigt vetenskapligt)
  • 121.
    Andersson, Ken G.
    et al.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Ståhl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR: 2377 affibody molecule labeled with 99mTc using a peptide-based cysteine-containing chelator2016Ingår i: International journal of oncology, ISSN 1791-2423, Vol. 49, nr 6, s. 2285-2293Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide 99mTc should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with 99mTc using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, 99mTc-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that 99mTc-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6±1 and 2.5±0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8±0.4 and 8±3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of 99mTc-labeled ZEGFR:2377 for imaging of EGFR in vivo.

  • 122. Andersson, Ken G.
    et al.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Malm, Magdalena
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lofblom, John
    Stahl, Stefan
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Comparative evaluation of 111In-labeled NOTA‑conjugated affibody molecules for visualization of HER3 expression in malignant tumors2015Ingår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 34, nr 2, s. 1042-1048Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Expression of human epidermal growth factor receptor type 3 (HER3) in malignant tumors has been associated with resistance to a variety of anticancer therapies. Several anti-HER3 monoclonal antibodies are currently under pre-clinical and clinical development aiming to overcome HER3-mediated resistance. Radionuclide molecular imaging of HER3 expression may improve treatment by allowing the selection of suitable patients for HER3-targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. In a recent study, we selected affibody molecules with affinity to HER3 at a low picomolar range. The aim of the present study was to develop an anti-HER3 affibody molecule suitable for labeling with radiometals. The HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA HER3-specific affibody molecules were labeled with indium-111 (In-111) and assessed in vitro and in vivo for imaging properties using single photon emission computed tomography (SPECT). Labeling of HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA with In-111 provided stable conjugates. In vitro cell tests demonstrated specific binding of the two conjugates to HER3-expressing BT-474 breast carcinoma cells. In mice bearing BT-474 xenografts, the tumor uptake of the two conjugates was receptor-specific. Direct in vivo comparison of In-111-HEHEHE-Z08698-NOTA and In-111-HEHEHE-Z08699-NOTA demonstrated that the two conjugates provided equal radioactivity uptake in tumors, although the tumor-to-blood ratio was improved for In-111-HEHEHE-Z08698-NOTA [12 +/- 3 vs. 8 +/- 1,4 h post injection (p.i)] due to more efficient blood clearance. In-111-HEHEHE-Z08698-NOTA is a promising candidate for imaging of HER3-expression in malignant tumors using SPECT. Results of the present study indicate that this conjugate could be used for patient stratification for anti-HER3 therapy.

  • 123. Andersson, PM
    et al.
    Lundstedt, T
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hierarchical experimental design exemplified by QSAR evaluation of a chemical library directed towards the melanocortin 4 receptor2002Ingår i: JOURNAL OF CHEMOMETRICS, Vol. 16, s. 490-Artikel i tidskrift (Refereegranskat)
  • 124. Andersson, PM
    et al.
    Sjostrom, M
    Wold, S
    Lundstedt, T
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Strategies for subset selection of parts of an in-house chemical library2001Ingår i: J CHEMOMETRICS, Vol. 15, s. 353-Artikel i tidskrift (Refereegranskat)
  • 125.
    Andren, Per
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Lab. för Biologisk och Medicinsk Masspektrometri.
    Svensson, Marcus
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Lab. för Biologisk och Medicinsk Masspektrometri.
    Skold, Karl
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Lab. för Biologisk och Medicinsk Masspektrometri.
    Svenningsson, Per
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Peptidomics-based Discovery of Endogenous Neuropeptides in the Brain2003Ingår i: Emerging Technologies in Protein and Genomic Material, Elsevier Science B.V, Amsterdam , 2003, s. 155-167Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 126. Andreou, Dimitrios
    et al.
    Saetre, Peter
    Werge, Thomas
    Andreassen, Ole A.
    Agartz, Ingrid
    Sedvall, Göran C.
    Hall, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Terenius, Lars
    Jonsson, Erik G.
    d-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians2012Ingår i: European Archives of Psychiatry and Clinical Neuroscience, ISSN 0940-1334, E-ISSN 1433-8491, Vol. 262, nr 7, s. 549-556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.

  • 127.
    Aneja, Babita
    et al.
    Jamia Millia Islamia, Dept Biosci, New Delhi 110025, India;Jamia Millia Islamia, Dept Chem, New Delhi 110025, India.
    Khan, Nashrah Sharif
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India;Jamia Millia Islamia, Dept Biotechnol, New Delhi 110025, India.
    Khan, Parvez
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India.
    Queen, Aarfa
    Jamia Millia Islamia, Dept Chem, New Delhi 110025, India.
    Hussain, Afzal
    King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh 11451, Saudi Arabia.
    Rehman, Md. Tabish
    King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh 11451, Saudi Arabia.
    Alajmi, Mohamed F.
    King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh 11451, Saudi Arabia.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Ali, Sher
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India.
    Hassan, Md. Imtaiyaz
    Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India.
    Abid, Mohammad
    Jamia Millia Islamia, Dept Biosci, New Delhi 110025, India.
    Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis2019Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 163, s. 840-852Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 mu M, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.

  • 128.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Development of carbon-11 labelled PET tracers-radiochemical and technological challenges in a historic perspective2015Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, nr 3, s. 65-72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of positron emission tomography (PET) from being an exclusive and expensive research tool at major research institutes to a clinically useful modality found at most major hospitals around the world is largely dependent on radiochemistry and synthesis technology achievements by a few pioneer researchers starting their PET careers 40 to 50years ago. Especially, the introduction of [C-11]methyl iodide resulted in a quantum jump in the history of PET tracer development enabling the smooth labelling of a multitude of useful tracers. A more recent and still challenging methodological improvement is transition metal mediated C-11-carbonylations, having a large synthetic potential that has, however, not yet been realized in the clinical setting. This mini-review focuses on the history of carbon-11 radiochemistry and related technology developments and the role this played in PET tracer developments, especially emphasizing radiolabelling of endogenous compounds. A few examples will be presented of how the use of radiolabelled endogenous substances have provided fundamental information of in vivo biochemistry using the concept of position-specific labelling in different positions in the same molecule.

  • 129.
    Antoni, Gunnar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Estrada, Sergio
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Axelsson, Jan
    Carlson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Lindsjö, Lars
    Kero, Tanja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Granstam, Sven-Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Rosengren, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Vedin, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Wassberg, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    In Vivo Visualization of Amyloid Deposits in the Heart with 11C-PIB and PET2013Ingår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, nr 2, s. 213-220Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-11C]2-(4′-methylamino-phenyl)-6-hydroxybenzothiazole (11C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of 11C-PIB PET in systemic amyloidosis affecting the heart.

    Methods:

    Patients (n = 10) diagnosed with systemic amyloidosis—including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type—and healthy volunteers (n = 5) were investigated with PET/CT using 11C-PIB to study cardiac amyloid deposits and with 11C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention.

    Results:

    Myocardial 11C-PIB uptake was visually evident in all patients 15–25 min after injection and was not seen in any volunteer. A significant difference in 11C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with 11C-PIB. No correlation between 11C-PIB retention index and myocardial blood flow as measured with 11C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient.

    Conclusion:

    11C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

  • 130. Antoni, Gunnar
    et al.
    Omura, H
    Bergström, Mats
    Furuya, Y
    Moulder, R
    Roberto, A
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Watanabe, Y
    Långström, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Synthesis of l-2,4-Diamino[4-11C]butyric acid and its use in some In vitro and In vivo tumour models1997Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 24, nr 6, s. 595-601Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    l-2,4-Diamino[4-11C]butyric acid (DAB) was synthesized by an enzyme catalysed carrier added (0.1 μmol KCN) reaction of hydrogen [11C]cyanide with O-acetyl-l-serine followed by reduction. l-[11C]DAB was obtained with a radiochemical purity higher than 96% and with a decay corrected radiochemical yield of 30–40% within a 32 min reaction time. The enantiomeric excess was 98%. The uptake of l-[11C]DAB was investigated in multicellular aggregates of six different cell lines and animal tumour models. l-[11C]DAB is potentially useful for the assessment of pharmacokinetics of l-DAB in vivo for part of its evaluation as an antitumoural agent, although its use for diagnostic purposes seems limited.

  • 131.
    Antoni, Gunnar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Selvaraju, Ramkumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Borg, Beatrice
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Asplund, Veronika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Estrada, Sergio
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    5-Fluoro-[beta-C-11]-L-tryptophan is a functional analogue of 5-hydroxy-[beta-C-11]-L-tryptophan in vitro but not in vivo2013Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 56, nr S1, s. S367-S367Artikel i tidskrift (Övrigt vetenskapligt)
  • 132. Antoni, Gunnar
    et al.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Hall, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Molecular Imaging of Transporters with Positron Emission Tomography2009Ingår i: Transporters as Targets for Drugs, Berlin: Springer, 2009, Vol. 4, s. 155-186Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Positron emission tomography (PET) visualization of brain components in vivo is a rapidly growing field. Molecular imaging with PET is also increasingly used in drug development, especially for the determination of drug receptor interaction for CNS-active drugs. This gives the opportunity to relate clinical efficacy to per cent receptor occupancy of a drug on a certain targeted receptor and to relate drug pharmacokinetics in plasma to interaction with target protein. In the present review we will focus on the study of transporters, such as the monoamine transporters, the P-glycoprotein (Pgp) transporter, the vesicular monoamine transporter type 2, and the glucose transporter using PET radioligands. Neurotransmitter transporters are presynaptically located and in vivo imaging using PET can therefore be used for the determination of the density of afferent neurons. Several promising PET ligands for the noradrenaline transporter (NET) have been labeled and evaluated in vivo including in man, but a really useful PET ligand for NET still remains to be identified. The most promising tracer to date is (S,S)-[18F]FMeNER-D2. The in vivo visualization of the dopamine transporter (DAT) may give clues in the evaluation of conditions related to dopamine, such as Parkinson's disease and drug abuse. The first PET radioligands based on cocaine were not selective, but more recently several selective tracers such as [11C]PE2I have been characterized and shown to be suitable as PET radioligands. Although there are a large number of serotonin transporter inhibitors used today as SSRIs, it was not until very recently, when [11C]McN5652 was synthesized, that this transporter was studied using PET. New candidates as PET radioligands for the SERT have subsequently been developed and [11C]DASB and [11C]MADAM and their analogues are today the most promising ligands. The existing radioligands for Pgp transporters seem to be suitable tools for the study of both peripheral and central drug–Pgp interactions, although [11C]verapamil and [18F]fluoropaclitaxel are probably restricted to use in studies of the blood–brain barrier. The vesicular monoamine transporter 2 (VMAT2) is another interesting target for diagnostic imaging and [11C]DTBZ is a promising tracer. The noninvasive imaging of transporter density as a function of disease progression or availability following interaction with blocking drugs is highlighted, including the impact on both development of new therapies and the process of developing new drugs. Although CNS-related work focusing on psychiatric disorders is the main focus of this review, other applications of PET ligands, such as diagnosis of cancer, diabetes research, and drug interactions with efflux systems, are also discussed. The use of PET especially in terms of tracer development is briefly described. Finally, it can be concluded that there is an urgent need for new, selective radioligands for the study of the transporter systems in the human brain using PET.

  • 133.
    Anwar, J.
    et al.
    Univ Agr, Dept Agr Chem, Peshawar 25100, Pakistan..
    Muhammad, Taj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Iqbal, Z.
    Univ Agr, Dept Agr Chem, Peshawar 25100, Pakistan..
    Fungi as a source for antibacterial compounds2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 134.
    Appukkuttan, P
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
    van der Eycken, E
    Micro-wave assisted natural products chemistry2006Ingår i: Top. Curr. Chem., nr 266, s. 1-49Artikel i tidskrift (Refereegranskat)
  • 135.
    Appukkuttan, Prasad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Axelsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Van der Eycken, Erik
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up2008Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, nr 39, s. 5625-5628Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)(6) as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in promoting the conversions in a mere 10-20 min with various (hetero)aryl iodides, bromides and chlorides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed successfully. (C) 2008 Elsevier Ltd. All rights reserved.

  • 136.
    Appukkuttan, Prasad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Dehaen, Wim
    Van der Eycken, Erik
    Microwave-assisted transition-metal-catalyzed synthesis of N-shifted and ring-expanded buflavine analogues2007Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 13, nr 22, s. 6452-6460Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Two novel and efficient strategies for the synthesis of hitherto unknown N-shifted and ring-expanded buflavine analogues are presented. Construction of the medium-sized ring system of the title molecules, a difficult task due to the high activation energy needed for the ring-closure with the additional rigidity imposed by the biaryl skeleton, was achieved by using Suzuki-Miyaura biaryl coupling and a ring-closing metathesis reaction as the key steps. The combination of a second-generation Grubbs catalyst and microwave irradiation proved to be highly useful in generating the otherwise difficult to obtain medium-sized ring system of the buflavine analogues.

  • 137.
    Appukkuttan, Prasad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Van der Eycken, Erik
    Recent developments in microwave-assisted, transition-metal-catalysed C-C and C-N bond-forming reactions2008Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 7, s. 1133-1155Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    A selective over-view of the recent developments of microwave-assisted, transition-metal-catalysed C-C and C-N bond-forming reactions is presented. Microwave-assisted chemistry is a comparatively novel technique in the present-day synthetic world and has recently grown in an exponential manner, stretching from academia to a widely practiced technique in industry. Transition-metal-catalysed C-C and C-N bond-forming reactions represent one of the most interesting and well-investigated type of microwave-assisted reactions, evident from the plethora of available literature and patents in this area. Given the large number of articles published on the subject, we have made a very concise selection from the recent literature, covering manuscripts dealing with the subject from the period of the end 2004 until the first part of 2007.

  • 138.
    Arefalk, Anna
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    New Methods for the Synthesis of 3-Substituted 1-Indanones: A Palladium-Catalyzed Approach2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In medicinal chemistry, there is a constant need for new preparative methods, both to make the synthesis process more effective, and to increase the accessibility to a wide variety of compounds. A number of different approaches can be used to attain these goals. Transition metal catalysis is generally performed under mild conditions, providing both regio- and chemoselective reactions. Thus, it offers an attractive means of preparation of complex drug candidates. Two additional methodologies used to increase the preparative efficiency are one-pot protocols and controlled microwave heating. One-pot and multi-component reactions are less time consuming than step-by-step reactions, and microwave heating has been used to considerably shorten the reaction times.

    This thesis describes a new palladium-catalyzed, one-pot reaction producing racemic acetal-protected 3-hydroxy-1-indanones from ethylene glycol vinyl ether and triflates of salicylic aldehydes. The triflates were prepared using controlled microwave heating. The reaction sequence starts with a regioselective internal Heck coupling, followed by an annulation cascade. By including secondary amines in the reaction mixture, the reaction was further developed into a three-component reaction delivering racemic acetal-protected 3-amino-1-indanones. This new method was utilized for the synthesis of primary, secondary and tertiary aminoindanones. Finally, by using enantiopure t-butyl sulfinyl imines, derived from salicylic aldehyde triflates and ethylene glycol vinyl ether as starting materials in a closely related type of palladium coupling–annulation sequence, a stereoselective protocol providing enantiomerically pure 3-amino-1-indanones was developed. To demonstrate an application in medicinal chemistry, the enantiopure 3-amino-1-indanones were incorporated as P2 and/or P2´ substituents into active HIV-1 protease inhibitors.

    Delarbeten
    1. Fast Synthesis of Aryl Triflates with Controlled Microwave Heating
    Öppna denna publikation i ny flik eller fönster >>Fast Synthesis of Aryl Triflates with Controlled Microwave Heating
    2002 (Engelska)Ingår i: Organic Letters, ISSN 1523-7060, Vol. 4, nr 7, s. 1231-1233Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-93597 (URN)
    Tillgänglig från: 2005-10-20 Skapad: 2005-10-20 Senast uppdaterad: 2013-07-04Bibliografiskt granskad