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Assessment of receptor occupancy-over-time of two dopamine transporter inhibitors by [C-11]CIT and target controlled infusion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
2011 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 2, 100-106 p.Article in journal (Refereed) Published
Abstract [en]

Introduction. Occupancy-over-time was determined for two dopamine transporter (DAT) inhibitors through modeling of their ability to displace the PET ligand [C-11]CIT. The tracer was held at a pseudo steady state in a reference tissue by target controlled infusion. Methods. Rhesus monkeys (n = 5) were given [C-11]CIT and studied with a PET scanner. Tracer uptake in the reference tissue cerebellum was held at a pseudo steady state by use of target controlled infusion. The pharmacokinetics/pharmacodynamics (PK/PD) of [C-11]CIT was assessed through the simplified reference tissue model (SRTM). Bupropion (n = 2) and GBR-12909 (n = 2) receptor occupancies were estimated through modeling of their effects on [C-11]CIT displacement. Results. There was a high uptake of [C-11]CIT in striatum, which contains a high DAT density. The reference tissue cerebellum had a comparatively low uptake. The modeling of [C-11]CIT PK/PD properties in striatum showed high binding potential (BP = 5.34 +/- 0.78). Both DAT inhibitors caused immediate displacement of [C-11]CIT after administration. The occupancy-over-time was modeled as a mono-exponential function, describing initial maximal occupancy (Occ(0)) and rate of ligand-receptor dissociation (k(off)). GBR-12909 showed irreversible binding (k(off) = 0) after an initial occupancy of 76.1%. Bupropion had a higher initial occupancy (84.5%) followed by a release half-life of 33 minutes (k(off) = 0.021). Conclusions. The proposed model can be used for assessment of in-vivo occupancy-over-time of DAT ligands by use of target controlled infusion of [C-11]CIT. The concept of assessing drug-receptor interactions by studying perturbations of a PET tracer from a pseudo steady state can be transferred to other CNS systems.

Place, publisher, year, edition, pages
2011. Vol. 116, no 2, 100-106 p.
Keyword [en]
CCIP, [C-11]CIT, DAT inhibitor, SRTM, TCI
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-152804DOI: 10.3109/03009734.2011.563878ISI: 000289467100003PubMedID: 21443419OAI: oai:DiVA.org:uu-152804DiVA: diva2:414464
Available from: 2011-05-03 Created: 2011-05-02 Last updated: 2012-03-20Bibliographically approved

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