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Pre-Clinical Evaluation of a Novel Radiotracer for the Diagnosis of DVT and Pulmonary Embolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are different aspects of a single condition, venous thrombo-embolic disease (VTE), a major cause of morbidity and mortality in the western world. Rapid diagnosis is critical, as timely medical intervention can have a substantial beneficial effect on the mortality rate.

Irrespective of its presentation, VTE is a difficult disease to diagnose. Pathologies unrelated to VTE can give rise to a clinical presentation similar to DVT or PE, resulting in a false positive diagnosis. This raises the risk of a patient being treated inappropriately. Therefore, there is a need for an agent that has high specificity and sensitivity for the detection of active blood clots, which are amenable to treatment by anticoagulant and/or thrombolytic therapy.

This work describes the pre-clinical efficacy studies performed on one such agent, 99mTc-NC100668. 99mTc-NC100668 is a substrate for factor XIIIa and as a potential physiological, rather than anatomical, marker of VTE it is hoped it will not give rise to the false negative and positive diagnoses that are inherent in the currently available diagnostic techniques, such as the ventilation perfusion (V/Q) scan, multidetector computer tomography or ultrasound.

It is reported in this work that 99mTc-NC100668 uptake and retention in blood clot was rapid and maintained over at least a 4 hour period in a rat model of DVT. Anticoagulant and thrombolytic therapies commonly used to treat thrombosis did not seriously impair the ability of 99mTc-NC100668 to detect thrombi. No significant tissue retention, which could interfere with the ability to image thrombi in vivo, was observed. Biodistribution and plasma clot uptake studies showed that 99mTc complex of gly-NC100194, the major metabolite of 99mTc-NC100668, would be unlikely to affect adversely the clinical utility of the test substance.

The in vitro uptake of 99mTc-NC100668 into forming plasma clots indicated that retention into human blood clots would be comparable with the observations made in the rat preclinical models.

The uptake of 99mTc-NC100668 in vitro and in vivo was much greater than could be accounted for by physical entrapment into the forming blood clots. The reduced uptake of a biologically inactive analogue of 99mTc-NC100668 both in vitro and in vivo indicated that the blood clot uptake and retention of 99mTc-NC100668 was mediated by factor XIIIa.

In conclusion, 99mTc-NC100668 might be useful in the detection of thrombo embolism.

Place, publisher, year, edition, pages
Uppsala: Institutionen för onkologi, radiologi och klinisk immunologi , 2006. , p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 203
Keywords [en]
Radiology
Keywords [sv]
Radiologisk forskning
Identifiers
URN: urn:nbn:se:uu:diva-7321ISBN: 91-554-6726-1 (print)OAI: oai:DiVA.org:uu-7321DiVA, id: diva2:169275
Public defence
2006-12-08, Föreläsningssalen, Röntgen, Ing. 70, 1 tr, Akademiska sjukhuset, UPPSALA, 13:15
Opponent
Supervisors
Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2011-05-19Bibliographically approved
List of papers
1. Tc-99m-NC100668, a new tracer for imaging venous thromboemboli: pre-clinical biodistribution and incorporation into plasma clots in vivo and in vitro
Open this publication in new window or tab >>Tc-99m-NC100668, a new tracer for imaging venous thromboemboli: pre-clinical biodistribution and incorporation into plasma clots in vivo and in vitro
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2006 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 33, no 11, p. 1258-1265Article in journal (Refereed) Published
Abstract [en]

Purpose: Tc-99m-NC100668 is a new radiotracer being developed to aid the diagnosis of thromboembolism. The structure of NC100668 is similar to a region of human alpha(2)-antiplasmin, which is a substrate for factor XIIIa (FXIIIa). The purpose of this study was to confirm the uptake of Tc-99m-NC100668 into forming plasma clot and to establish the biodistribution of Tc-99m-NC100668 in Wistar rats.

Methods: The in vitro plasma clot uptake of Tc-99m-NC100668 and other compounds with known affinities to FXIIIa was measured using a plasma clot assay. The biodistribution and blood clot uptake of radioactivity of Tc-99m-NC100668 in normal Wistar rats and those bearing experimentally induced deep vein thrombi were investigated.

Results: The in vitro uptake of Tc-99m-NC100668 was greater than that for [C-14] dansyl cadaverine, a known substrate of FXIIIa in the plasma clot assay. The biodistribution of Tc-99m-NC100668 in male and female Wistar rats up to 24 h p.i. showed that radioactivity was rapidly excreted, predominantly into the urine, with very little background tissue retention. In vivo the uptake and retention of Tc-99m-NC100668 into the blood clot was greater than could be accounted for by non-specific accumulation of the radiotracer within the blood clot.

Conclusion: Tc-99m-NC100668 was retained by plasma clots in vitro and blood clots in vivo. No significant tissue retention which could interfere with the ability to image thrombi in vivo was observed. This evidence suggests that Tc-99m-NC100668 might be useful in the detection of thromboembolism.

Keywords
biodistribution, molecular imaging, Tc-99m-NC100668, thrombus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95163 (URN)10.1007/s00259-006-0091-9 (DOI)000241522600003 ()16804686 (PubMedID)
Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2017-12-14Bibliographically approved
2. The in vivo and in vitro metabolic profile of 99mTc-NC100668, a new tracer for imaging venous thrombo-embolism: Identification and biodistribution of the principal radiolabelled metabolite.
Open this publication in new window or tab >>The in vivo and in vitro metabolic profile of 99mTc-NC100668, a new tracer for imaging venous thrombo-embolism: Identification and biodistribution of the principal radiolabelled metabolite.
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2006 In: Drug Metab Dispos, ISSN 0090-9556, Vol. 34, no 7, p. 1128-35Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-95164 (URN)
Available from: 2006-11-17 Created: 2006-11-17Bibliographically approved
3. 99mTc-NC100668, an agent for imaging venous thromboembolism: The effect of anticoagulant or thrombolytic therapy on the uptake and retention of radioactivity in blood clots in vivo
Open this publication in new window or tab >>99mTc-NC100668, an agent for imaging venous thromboembolism: The effect of anticoagulant or thrombolytic therapy on the uptake and retention of radioactivity in blood clots in vivo
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2007 (English)In: Nuclear medicine communications, ISSN 0143-3636, E-ISSN 1473-5628, Vol. 28, no 1, p. 55-62Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The purpose of this study was to evaluate the uptake of Tc-NC100668 into blood clots and elucidate the potential for medications commonly used to treat thromboembolism to interfere with the uptake and retention of Tc-NC100668. METHODS: Tc-NC100668 in vivo uptake and retention in a range of blood clot of various ages (up to 4 h old) and in the presence of anticoagulants or thrombolytic therapies was measured in a rat model of deep vein thrombosis. RESULTS: Tc-NC100668 was rapidly absorbed into and retained by blood clots and was not significantly affected by the presence of unfractionated or low molecular weight heparin or thrombin inhibitor. Tissue plasminogen activator reduced the uptake of Tc-NC100668 into blood clot by a factor of 3 when adjusted to allow for changes in the weight of the blood clot. CONCLUSIONS: This study has demonstrated that the uptake and retention of Tc-NC100668 into blood clots in the rat model of deep vein thrombosis is rapid and maintained over at least a 4 h post-injection period. It has been shown that Tc-NC100668 is retained in blood clots even in the presence of therapeutic doses of those anticoagulant and thrombolytic therapies typically used to treat pulmonary embolism and venous thrombosis.

Keywords
99mTc-NC100668, Anticoagulants, Biodistribution, Thrombus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95165 (URN)10.1097/01.mnm.0000243378.34131.01 (DOI)000243360400010 ()17159550 (PubMedID)
Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2017-12-14Bibliographically approved
4. The biodistribution of NC100668 and the effect of excess NC100668 on the biodistribution and kidney retention of Tc-99m-NC100668 in the rat
Open this publication in new window or tab >>The biodistribution of NC100668 and the effect of excess NC100668 on the biodistribution and kidney retention of Tc-99m-NC100668 in the rat
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2007 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 34, no 3, p. 315-323Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: (99m)Tc-NC100668 is being developed to aid the diagnosis of thromboemboli. The purpose of this study was to investigate if the presence of excess NC100668 interferes with the biodistribution and blood clot uptake of (99m)Tc-NC100668. The secondary aim was to investigate the causes underlying the kidney retention of (99m)Tc-NC100668. METHODS: The uptake of a (14)C-labelled analogue of NC100668, as well as (99m)Tc-NC100668, into plasma (in vitro) and blood (in vivo) clots was determined. The biodistribution of (99m)Tc-NC100668 at a range of NC100668 doses was studied in normal Wistar rats and those bearing experimentally induced deep venous thrombosis. The biodistribution of a negative control peptide and (99m)Tc-NC100668 plus L-lysine was studied in healthy male Wistar rats. RESULTS: The biodistribution as well as plasma clot uptake of [Asn-U-(14)C]NC100668 and (99m)Tc-NC100668 was similar. Apart from some reduction in kidney retention, the biodistribution and uptake of radioactivity into the blood clot were not significantly affected by the presence of up to 1000 times the clinical dose of NC100668. Kidney retention of radioactivity could be more effectively reduced by coadministration of 889 microg/kg NC100668 than 450 mg/kg L-lysine. A negative control peptide with no affinity for FXIIIa demonstrated very little kidney retention. CONCLUSIONS: The biodistribution and blood clot uptake of (99m)Tc-NC100668 and [Asn-U-(14)C]NC100668 are similar. With the exception of the kidneys, (99m)Tc-NC100668 biodistribution and blood clot uptake are unaffected by the presence of unlabelled NC100668. The kidney retention of radioactivity is probably due to transglutaminase activity and, to a lesser extent, nonspecific charge-mediated endocytosis.

Keywords
99mTc-NC100668, Biodistribution, Ligand dose, Thrombus, Rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95166 (URN)10.1016/j.nucmedbio.2007.01.008 (DOI)000245513800011 ()17383581 (PubMedID)
Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2017-12-14Bibliographically approved

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