Synthesis and evaluation of high affinity, aryl-substituted [18F]fluoropropylbenzamides for dopamine D-2 receptor studies

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 ($\text{St}\text{Cb}$) 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.