Assessment of receptor occupancy-over-time of two dopamine transporter inhibitors by [C-11]CIT and target controlled infusion
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
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.
CCIP, [C-11]CIT, DAT inhibitor, SRTM, TCI
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-152804DOI: 10.3109/03009734.2011.563878ISI: 000289467100003PubMedID: 21443419OAI: oai:DiVA.org:uu-152804DiVA: diva2:414464