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

被引:13
作者
Kiesewetter, DO
Carson, RE
Jagoda, EM
Endres, CJ
Der, MG
Herscovitch, P
Eckelman, WC
机构
[1] National Institutes of Health, Positron Emission Tomography Dept., Warren G. Magnusen Clinical Center, Bethesda, MD 20892-1180
[2] NIH/CC/ PET, Building 10, Bethesda, MD 20892-1180
关键词
D O I
10.1016/S0968-0896(97)00100-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:1555 / 1567
页数:13
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