Synthesis and in Vitro and in Vivo Evaluation of 18F-Labeled Positron Emission Tomography (PET) Ligands for Imaging the Vesicular Acetylcholine Transporter

A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (+/-)-trans-2-Hydroxy-3-(4-(4-[F-18]fluorobenzoyl)piperidino)tetralin (9e) has K-i values of 2.70 nM for VAChT, 191 nM for sigma(1), and 251 nM for sigma(2). The racemic precursor (9d) was resolved via chiral HPLC, and (+/-)-[F-18]9e, (-)-[F-18]9e, and (+)-[F-18]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [F-18]/F- and Kryptofix/K2CO3 in DMSO with radiochemical yields of similar to 50-60% and specific activities of >2000 mCi/umol. (-)-[F-18]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[F-18]9e in putamen versus cerebellum at 2 h p.i. (-)-[F-18]9e has potential to be a PET tracer for clinical imaging of the VAChT.