Carbon-11 epidepride: A suitable radioligand for PET investigation of striatal and extrastriatal dopamine D-2 receptors

Epidepride {(S)-(-)-N ([1-ethyl-2-pyrrolidinyl]methyl)-5-iodo-2,3-dimethoxy benzamide} binds with a picomolar affinity (K-i = 24 pM) to the dopamine D- 2 receptor. Iodine-123-labeled epidepride has been used previously to study striatal and extrastriatal dopamine D-2 receptors with single photon emiss ion computed tomography (SPECT), Our aim was to label epidepride with carbo n-ii for comparative quantitative studies between positron emission tomogra phy (PET) and SPECT. Epidepride was synthesized from its bromo-analogue FLB 457 via the corresponding trimethyl-tin derivative. In an alternative synt hetic pathway, the corresponding substituted benzoic acid was reacted with the optically pure aminomethylpyrrolidine-derivative. Demethylation of epid epride gave the desmethyl-derivative, which was reacted with [C-11]methyl t riflate. Total radiochemical yield was 40-50% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was 37-111 G Bq/mu mol (1,000-3,000 Ci/mmol). Human postmortem whole-hemisphere autoradi ography demonstrated dense binding in the caudate putamen, and also in extr astriatal areas such as the thalamus and the neocortex. The binding was inh ibited by unlabeled raclopride. PET studies in a cynomolgus monkey demonstr ated high uptake in the striatum and in several extrastriatal regions. At 9 0 min after injection, uptake in the striatum, thalamus and neocortex was a bout 11, 4, and 2 times higher than in the cerebellum, respectively. Pretre atment experiment with unlabeled raclopride (1 mg/kg) inhibited 50-70% of [ C-11]epidepride binding. The fraction of unchanged [C-11]epidepride in monk ey plasma determined by a gradient high performance liquid chromatography ( HPLC) method was about 30% of the total radioactivity at 30 min after injec tion of [C-11]epidepride. The availability of [C-11]epidepride allows the P ET-verification of the data obtained from quantitation studies with SPECT. (C) 1999 Elsevier Science Inc. All rights reserved.