title: Binding characteristics of high-affinity dopamine D2/D3 receptor agonists, 11C-PPHT and 11C-ZYY-339 in rodents and imaging in non-human primates by PET.
abstract: We have evaluated the in vitro autoradiographic binding characteristics and in vivo brain distribution of two high-affinity dopamine D2/D3 receptor agonists, (+/-)-2-(N-phenethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-PPHT) and (+/-)-2-(N-cyclohexylethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-ZYY-339) in rodents and in monkeys using positron emission tomography (PET). In vitro autoradiograms in rat brain slices with (11)C-PPHT and 11C-ZYY-339 revealed binding to dopaminergic regions in the striata, which was substantially (>90%) displaced by 10 microM sulpiride. Striatal binding was also removed in the presence of 5-guanylylimidophosphate (Gpp(NH)p), indicative of binding of these radiotracers to the high-affinity (HA) state. The results of in vivo studies in rats exhibited binding of the two radiotracers to the striata (striata/cerebellum approached 2 in 30 min). The regional selectivity to the striata was reduced by preadministration of haloperidol. PET studies in male rhesus monkeys using an ECAT EXACT HR+ scanner indicated localization of 11C-PPHT and 11C-ZYY-339 in the striata and thalamus. Striata to cerebellum and thalamus to cerebellum ratios were low (1.5 and 1.3, respectively, at 30 min postinjection) for both 11C-PPHT and 11C-ZYY-339, apparently due to the slower nonspecific clearance from cerebellum. These findings with 11C-PPHT and 11C-ZYY-339 indicate the possibility of in vivo imaging of high-affinity state of dopamine D2/D3 receptors in both the striata and the thalamus.
authors.affiliation: Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, California 92697, USA. mukherjj@uci.edu
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Tanjore K
authors.initials: TK
authors.lastname: Narayanan
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Christian
authors.forename: Bingzhi
authors.initials: B
authors.lastname: Shi
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Yang
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism; D001923:Brain Chemistry; D001931:Brain Mapping / Q000379:methods; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics*; D002247:Carbon Isotopes / Q000097:blood / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D008297:Male; D010627:Phenethylamines / Q000097:blood / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D002219:Carbamates; D002247:Carbon Isotopes; C493595:Drd3 protein, rat; D010627:Phenethylamines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C011994:pirimicarb; D006165:Guanylyl Imidodiphosphate; C011799:5-hydroxy-2-N,N-dipropylaminotetralin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C041369:2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin