title: PET radiotracer development for imaging high-affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine-18 labeled aminotetralins in rodents.
abstract: Imaging the high-affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of18F-5-OH-FPPAT, and the newer18F-5-OH-FHXPAT and18F-7-OH-FHXPAT. Syntheses of18F-5-OH-FHXPAT and18F-7-OH-FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague-Dawley rats were used with the 3 radiotracers (74-111 kBq/cc). Competition with dopamine (1-100 nM) and Gpp(NH)p (10-50 µM) were carried out to demonstrate binding to dopamine D2 and D3 HA-states and binding kinetics of18F-5-OH-FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with18F-5-OH-FHXPAT to ascertain HA-state binding. PET/CT imaging in rats and wild type (WT) and D2 knock-out mice were carried out using18F-7-OH-FHXPAT (2-37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10-2min-1for18F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50-80% striatal binding with faster dissociation rates (5.0 × 10-2min-1), suggesting HA-state binding of18F-5-OH-FPPAT and18F-5-OH-FHXPAT. Striatal binding of18F-5-OH-FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA-state binding in vivo. PET binding ratios of18F-7-OH-FHXPAT in rat brain were ventral striatum/cerebellum = 2.09 and dorsal striatum/cerebellum = 1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane-bound HA-state of the dopamine receptor.
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging Center, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging Center, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Majji
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging Center, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging Center, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Cristian C
authors.initials: CC
authors.lastname: Constantinescu
authors.affiliation: Department of Nuclear Medicine, Kettering Medical Center, Dayton, Ohio, 45429, USA.
authors.forename: Tanjore K
authors.initials: TK
authors.lastname: Narayanan
authors.affiliation: Department of Nuclear Medicine, Kettering Medical Center, Dayton, Ohio, 45429, USA.
authors.forename: Bingzhi
authors.initials: B
authors.lastname: Shi
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging Center, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Mohamed T
authors.initials: MT
authors.lastname: Nour
authors.affiliation: Department of Radiological Sciences, Preclinical Imaging Center, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Pan
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000494:pharmacology; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000032:analysis*; D050637:Receptors, Dopamine D3 / Q000032:analysis*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes
keywords: PET; autoradiography; dopamine receptor; fluorinated agonists; high-affinity state