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

• Published in: Bioorganic & medicinal chemistry Vol. 5; no. 8; pp. 1555 - 1567
• Main Authors: Kiesewetter, D O, Carson, R E, Jagoda, E M, Endres, C J, Der, M G, Herscovitch, P, Eckelman, W C
• Format: Journal Article
• Language: English
• Published: England 01.08.1997
• Subjects: Anesthetics, Dissociative - pharmacology; Animals; Benzilates - chemistry; Benzilates - metabolism; Blood Proteins - metabolism; Fluorine Radioisotopes - chemistry; Fluorine Radioisotopes - metabolism; Ketamine - pharmacology; Macaca mulatta; Quinuclidines - chemistry; Quinuclidines - metabolism; Rats; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - metabolism; Tomography, Emission-Computed
• ISSN: 0968-0896
• DOI: 10.1016/S0968-0896(97)00100-4

We have developed a multistep radiochemical synthesis of two diastereomers of quinuclidinyl-4-[18F]-fluoromethyl-benzilate ([18F]-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)-[18F]-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)-[18F]-FMeQNB followed at 60 min by injection of unlabeled ligand and subsequent sacrifice at 120 min displaced 30-50% of radioactivity in the pons, medulla, and cerebellum, which contain a high proportion of M2 subtype. The most dramatic displacement and inhibition of uptake on coinjection of (R,S)-[18F]-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)-[18F]-FMeQNB is M2 selective in vivo. On the other hand, (R,R)-[18F]-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 pons. 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)-[18F]-FMeQNB being M1 selective in vivo.