Synthesis and in vitro evaluation of N-substituted aza-trozamicol analogs as vesicular acetylcholine transporter ligands

As dysfunction of cerebral cholinergic neurotransmission is one of the main features in patients with Alzheimer’s disease, in vivo imaging of the vesicular acetylcholine transporter (VAChT) can be of great value for the early diagnosis of this disease. Two series of positional isomers of m-iodobenzyltrozamicol (MIBT): 3-hydroxy-4-(N-phenylpiperazinyl)piperidine and 4-hydroxy-3-(N-phenylpiperazinyl)piperidine substituted by benzyl, aryl, alkyl or vinyl groups at the nitrogen have been synthesized. These compounds have been evaluated in vitro by competition studies and five compounds (N-benzyl derivatives) showed high affinity for the VAChT (11 nM < IC50 < 66 nM). These compounds will be soon radiolabeled with [125I] for further biological evaluation using single photon emission computed tomography (SPECT).