Dopamine D3 receptor binding of 18F‐fallypride: Evaluation using in vitro and in vivo PET imaging studies

Identification of dopamine D3 receptors (D3R) in vivo is important to understand several brain functions related to addiction. The goal of this work was to identify D3R binding of the dopamine D2 receptor (D2R)/D3R imaging agent, ¹⁸F‐fallypride. Brain slices from male Sprague‐Dawley rats (n = 6) and New Zealand White rabbits (n = 6) were incubated with ¹⁸F‐fallypride and D3R selective agonist (R)‐7‐OH‐DPAT (98‐fold D3R selective). Rat slices were also treated with BP 897 (68‐fold D3R selective partial agonist) and NGB 2904 (56‐fold D3R selective antagonist). In vivo rat studies (n = 6) were done on Inveon PET using 18‐37 MBq ¹⁸F‐fallypride and drug‐induced displacement by (R)‐7‐OH‐DPAT, BP 897 and NGB 2904. PET/CT imaging of wild type (WT, n = 2) and D2R knock‐out (KO, n = 2) mice were carried out with ¹⁸F‐fallypride. (R)‐7‐OH‐DPAT displaced binding of ¹⁸F‐fallypride, both in vitro and in vivo. In vitro, at 10 nM (R)‐7‐OH‐DPAT, ¹⁸F‐fallypride binding in the rat ventral striatum (VST) and dorsal striatum (DST) and rabbit nucleus accumbens were reduced by ～10–15%. At 10 μM (R)‐7‐OH‐DPAT all regions in rat and rabbit were reduced by ≥85%. In vivo reductions for DST and VST before and after (R)‐7‐OH‐DPAT were: low‐dose (0.015 mg kg^?1) DST ?22%, VST ?29%; high‐dose (1.88 mg kg^?1) DST ?58%, VST ?77%, suggesting D₃R/D₂R displacement. BP 897 and NGB 2904 competed with ¹⁸F‐fallypride in vitro, but unlike BP 897, NGB 2904 did not displace ¹⁸F‐fallypride in vivo. The D2R KO mice lacked ¹⁸F‐fallypride binding in the DST. In summary, our findings suggest that up to 20% of ¹⁸F‐fallypride may be bound to D3R sites in vivo. Synapse 69:577–591, 2015 . © 2015 Wiley Periodicals, Inc.