In vivo muscarinic binding selectivity of (R,S)- and (R,R)-[F-18]-fluoromethyl QNB

We have developed a multistep radiochemical synthesis of two diastereomers of quinuclidinyl-4-[F-18]-fluoromethylbenzilate ([F-18]-FMeQNB), a high-affinity ligand for muscarinic acetylcholine receptors. Previously, we have shown that the nonradioactive (R,R)-diastereomer displays an eightfold selectivity for M1 over M2 while the nonradioactive (R,S)-diastereomer displays a sevenfold selectivity for M2 over M1 in vitro. This paper reports the results of in vivo comparison studies. In the rat, uptake of (R,S)-[F-18]-FMeQNB was nearly uniform in all brain regions following the concentration of M2 subtype. The uptake was reduced by 36-54% in all brain regions on coinjection with 50 nmol of unlabeled ligand. An injection of (R,S)-[F-18]-FMeQNB followed at 60 min by injection of unlabeled ligand and subsequent sacrifice at 120 min displaced 30-50% of radioactivity in the pens, medulla, and cerebellum, which contain a high proportion of M2 subtype. The most dramatic displacement and inhibition of uptake on coinjection of (R,S)-[F-18]-FMeQNB was observed in the heart. In rhesus monkey, the compound showed prolonged uptake and retention in the brain. In the blood, the parent compound degraded rapidly to a single radiolabeled polar metabolite believed to be fluoride. Within 30 min the parent compound represented less than 5% of the plasma activity. Displacement with (R)-QNB was generally slow, but was more rapid from those tissues which contain a higher proportion of M2 subtype. The results are consistent with the hypothesis that (R,S)-[F-18]-FMeQNB is M2 selective in vivo. On the other hand, (R,R)-[F-18]-FMeQNB showed higher uptake in those brain regions containing a higher concentration of M1 subtype. Uptake in the heart at 60 min was much lower than that observed with the (R,S)-diastereomer. Inhibition of uptake on coinjection with unlabeled (R,S)-FMeQNB is only significant in the heart, thalamus, and pens. Inhibition of uptake on coinjection with unlabeled (R,R)-FMeQNB is quite uniform in all brain regions. Displacement with (R)-QNB shows a more varying amount displaced. These results are consistent with (R,R)-[F-18]-FMeQNB being M1 selective in vivo. Published by Elsevier Science Ltd.