title: Dopamine D3 receptor binding of (18)F-fallypride: Evaluation using in vitro and in vivo PET imaging studies.
abstract: 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, (18)F-fallypride. Brain slices from male Sprague-Dawley rats (n = 6) and New Zealand White rabbits (n = 6) were incubated with (18)F-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 (18)F-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 (18)F-fallypride. (R)-7-OH-DPAT displaced binding of (18)F-fallypride, both in vitro and in vivo. In vitro, at 10 nM (R)-7-OH-DPAT, (18)F-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 (18)F-fallypride in vitro, but unlike BP 897, NGB 2904 did not displace (18)F-fallypride in vivo. The D2R KO mice lacked (18)F-fallypride binding in the DST. In summary, our findings suggest that up to 20% of (18)F-fallypride may be bound to D3R sites in vivo.
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine, California, 92697.
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine, California, 92697.
authors.forename: Cristian C
authors.initials: CC
authors.lastname: Constantinescu
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine, California, 92697.
authors.forename: Angela T
authors.initials: AT
authors.lastname: Hoang
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine, California, 92697.
authors.forename: Taleen
authors.initials: T
authors.lastname: Jerjian
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine, California, 92697.
authors.forename: Divya
authors.initials: D
authors.lastname: Majji
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine, California, 92697.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Pan
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013045:Species Specificity; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D005449:Fluorenes; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; C116818:NGB 2904; D010879:Piperazines; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; C120565:BP 897; C031349:7-hydroxy-2-N,N-dipropylaminotetralin
keywords: 18F-fallypride; 7-OH-DPAT; BP 897; NGB 2904; PET imaging; addiction; dopamine D3 receptors