Ex vivo and in vivo evaluation of (2R,3R)-5-[(18)F]-fluoroethoxy- and fluoropropoxy-benzovesamicol, as PET radioligands for the vesicular acetylcholine transporter.

Molecular imaging of the vesicular acetylcholine transporter (VAChT) using positron emission tomography (PET) may provide insights into early diagnosis and better understanding of Alzheimer's disease. We further characterized the VAChT ligand (2R,3R)-5-FEOBV (1) and developed new fluoropropoxy analogues. Ex vivo studies of the new nonradiolabeled analogues (2R,3R)-5-FPOBV (2) (k(D) = 0.7 nM) and (2S,3S)-5-FPOBV (3) (k(D) = 8.8 nM) were performed in rat brain and showed an enantioselective inhibition of (-)-5-[(125)I]-IBVM uptake in striatum, cortex, and hippocampus (e.g., 74% for 2 and only 54% for 3 in the cortex). Radiochemical procedures were developed to produce [(18)F]1 and [(18)F]2 as potential imaging agent for the VAChT. The radiochemistry was carried out in a one step procedure, with radiolabeling yields of 17 and 2.6% (range: 1-5.4), respectively, nondecay corrected with good specific activity: 124-338 GBq/micromol. The radiochemical purity was greater than 98%. The biological (ex vivo and in vivo) properties of these radioligands were evaluated in rats and showed a low (less then 0.1% of the injected dose) and homogeneous brain uptake. The in vivo PET study of [(18)F]2 performed in baboon also revealed rapid defluorination as the main problem. Therefore [(18)F]1 and [(18)F]2 appear to be unsuitable for in vivo imaging of the VAChT using PET. (c) 2007 Wiley-Liss, Inc.