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-[ ¹⁸F]fluorobenzoyl)piperidino)tetralin (9e) has K _i values of 2.70 nM for VAChT, 191 nM for σ ₁ and 251 nM for σ ₂. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[ ¹⁸F]9e,(-)-[ ¹⁸F]9e, and (+)-[ ¹⁸F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [ ¹⁸F]/F- and Kryptofix/K ₂CO ₃ in DMSO with radiochemical yields of ∼50-60% and specific activities of >2000 mCi/μmol. (-)-[ ¹⁸F]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 (-)-[ ¹⁸F]9e in putamen versus cerebellum at 2 h p.i. (-)-[ ¹⁸F]9e has potential to be a PET tracer for clinical imaging of the VAChT.