Abstract
A derivative of tetrabenazine (TBZ, 1) containing an iodovinyl group (I‐TBZ, 3b) was prepared as a potential radiotracer for the vesicular monoamine transporter. The synthesis of 3a was achieved by ethynylation of TBZ. The ethynyl derivative 4, was converted to the corresponding vinylstannane 5. The vinylstannane intermediate was then treated with I~2~ in chloroform at room temperature, to afford the iodovinyl compound (3a, I‐TBZ). The no‐carrier‐added [^125^I]I‐TBZ (3b) was prepared by treating an ethanolic solution of 5 with sodium[^125^I]iodide in the presence of H~2~O~2~. Following i.v. injection, [^125^I]I‐TBZ (3b) can readily cross the blood brain barrier and localize in the brain (0.92 and 0.36% dose/organ, at 2 min and 30 min, respectively). However, no specific regional uptake of the ligand was observed. Subsequent biodistribution studies performed using two well resolved peaks obtained from chiral HPLC separation of 3b, demonstrated that Fraction I displayed higher brain uptake (0.6% dose/organ, 20 min) than the latter peak (Fraction II, 0.3% dose/organ, 20 min). Fraction I also exhibited a modest degree of specificity for the striatum which could be blocked by pretreatment with tetrabenazine. The high lipophilicity of 3a (P~o/b~ for Fraction 1 and II=1723 and 1395, respectively) may contribute to high nonspecific binding in vivo, and result in the low target/nontarget ratio observed for this compound. Iodovinyl‐TBZ analog 3b is a poor candidate as a SPECT imaging agent for the vesicular monoamine transporter.