N-(N-BENZYLPIPERIDIN-4-YL)-2-[F-18]FLUOROBENZAMIDE - A POTENTIAL LIGAND FOR PET IMAGING OF SIGMA-RECEPTORS

Four nitro-and fluorobenzamides (1-4) have been synthesized in good yi elds from nitro-and fluoro-substituted benzoyl chloride with 4-amino-1 -benzylpiperidine, In vitro studies showed that these compounds have h igh affinities to sigma receptors. N-(N-Benzylpiperidin-4-yl) 2-fluoro benzamide (3), in particular, bound to sigma receptors with high affin ity (K-i = 3.4 nM, guinea pig brain membranes) and high selectivity (s igma-2/sigma-1 = 120). It was, therefore, labeled with F-18 and evalua ted as a sigma receptor radioligand. N-(N-Benzylpiperidin-4-yl)-2-[F-1 8]fluorobenzamide (3a) was synthesized in one step by nucleophilic sub stitution of the 2-nitro precursor (1) with [F-18]fluoride in DMSO at 140 degrees C for 20 min followed by purification with HPLC in 4-10% y ield (decay corrected). The synthesis time was 90 min and the specific activity was 0.4-1.0 Ci/mu mol. Tissue distribution in mice revealed that the uptakes of 3a in the brain, heart, liver, lungs, spleen, kidn eys and small intestine were high, and the radioactivity in these orga ns remained constant from 60 to 120 min post-injection. The radioactiv ity in the bone did not significantly increase, suggesting in vivo def luorination may not be the major route of metabolism of 3a in mice. Bl ocking studies with haloperidol in rats indicated that the uptake of c ompound 3a in the rat brain was selective to haloperidol-sensitive sig ma sites, These results suggest that compound 3a is a potent sigma rec eptor radioligand and may be a potential ligand for PET imaging of sig ma receptors in humans. (C) 1997 Elsevier Science Inc.