Ex vivo and in vivo evaluation of (2R,3R)-5-[18F]-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 in-sights 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-FP0l3V (2) (k(D) = 0.7 nM) and (2S,3S)-5-FPOBV (3) (kD = 8.8 nM) were performed in rat brain and showed an enantioselective inhibition of (-)-5-[I-125]-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 [F-18]1 and [F-18]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/mu mol. 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 [F-18]2 performed in baboon also revealed rapid defluorination as the main problem. Therefore [F-18]1 and [F-18]2 appear to be unsuitable for in vivo imaging of the VAChT using PET.