title: Synthesis and evaluation of high affinity, aryl-substituted [18F]fluoropropylbenzamides for dopamine D-2 receptor studies.
abstract: The potent dopamine D-2 ligands (S)-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5(3- [18F]fluoropropyl)benzamide (18F-1) and (S)-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3- [18F]fluoropropyl)-6-hydroxybenzamide (18F-2) were prepared in high specific activity and 5-25% overall radiochemical yields. Benzamide 1 possessed a lower in vitro binding affinity for the D-2 receptor than salicylamide 2, but the in vivo striatal-to-cerebellar radioactivity concentration ratios (St/Cb) in rats and dogs were nearly identical for the two compounds. Compound 18F-2 was more lipophilic than 18F-1, and its increased penetration into and retention by striatal tissue was matched by an increase in non-specific binding in the cerebellum. Cerebral cortex radioactivity concentration levels in dogs were similar to cerebellum levels. The binding of 18F-labelled 1 and 2 displayed regional brain distribution patterns consistent with known dopamine D-2 receptor densities and was selectively blocked in the striatum of rats by dopamine D-2 antagonists. The binding of 18F-1 was found to be stereoselective, as the 18F-labelled (R)-enantiomer displayed no selective retention in the striatum of dogs. High levels of radioactivity were found in the bones of rats following the injection of 18F-1 and 18F-2, indicating that in vivo defluorination had occurred; however, no bone radioactivity was observed in dogs following the injection of these radioligands. Compound 18F-1 was displaced from the striatum of dogs by both d-amphetamine-stimulated dopamine release and haloperidol at doses of 1 and 0.5 mg/kg, respectively, while compound 18F-2 was displaced from the dog striatum only by haloperidol at these doses. The radioligand 18F-2 holds promise for positron emission tomography studies of the dopamine D-2 receptor system based upon its selective, potent binding and resistance to displacement by endogenous dopamine.
authors.affiliation: Research Medicine and Radiation Biophysics Division, University of California, Berkeley 94720.
authors.forename: C A
authors.initials: CA
authors.lastname: Mathis
authors.forename: J E
authors.initials: JE
authors.lastname: Bishop
authors.forename: J M
authors.initials: JM
authors.lastname: Gerdes
authors.forename: J M
authors.initials: JM
authors.lastname: Whitney
authors.forename: K M
authors.initials: KM
authors.lastname: Brennan
authors.forename: W J
authors.initials: WJ
authors.lastname: Jagust
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D004285:Dogs; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008297:Male; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012457:Salicylamides / Q000138:chemical synthesis* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D005462:Fluorine Radioisotopes; D017448:Receptors, Dopamine D2; D012457:Salicylamides