In vivo muscarinic binding selectivity of (R,S)- and (R,R)-[18F]-fluoromethyl QNB.
In vivo muscarinic binding selectivity of (R,S)- and (R,R)-[18F]-fluoromethyl QNB.
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(R,S)-和(R,R)-[18F]-氟甲基QNB的体内毒蕈碱结合选择性。
DOI：
10.1016/s0968-0896(97)00100-4
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发表时间：
1997
影响因子：
3.5
通讯作者：
Eckelman,WC
中科院分区：
文献类型：
--
作者：
Kiesewetter,DO;Carson,RE;Jagoda,EM;Endres,CJ;Der,MG;Herscovitch,P;Eckelman,WC
我们已经开发了一个多步放射化学合成奎宁环基-4-[18 F]-氟甲基二苯甲酸酯（[18 F]-FMeQNB），一个高亲和力的配体毒蕈碱乙酰胆碱受体的两个非对映体。以前，我们已经表明，非放射性的（R，R）-非对映异构体显示了八倍的选择性M1超过M2，而非放射性的（R，S）-非对映异构体显示了七倍的选择性M2超过M1在体外。本文报告了体内比较研究的结果。在大鼠中，随着M2亚型浓度的增加，（R，S）- [18 F]-FMeQNB在所有脑区的吸收几乎均匀。共注射50 nmol未标记配体后，所有脑区的摄取减少36-54%。注射（R，S）- [18 F]-FMeQNB，然后在60 min时注射未标记的配体，随后在120 min时处死，在脑桥、髓质和小脑中置换了30-50%的放射性，这些部位含有高比例的M2亚型。在心脏中观察到（R，S）- [18F]-FMeQNB共注射时最显著的置换和摄取抑制。在恒河猴中，该化合物在脑中的摄取和保留时间延长。在血液中，母体化合物迅速降解为单一放射性标记的极性代谢物，据信是氟化物。在30分钟内，母体化合物的血浆活性低于5%。用（R）-QNB置换通常是缓慢的，但从含有较高比例的M2亚型的那些组织中置换更快。结果与（R，S）- [18F]-FMeQNB在体内具有M2选择性的假设一致。另一方面，（R，R）- [18F]-FMeQNB在含有较高浓度的M1亚型的那些脑区域中显示出较高的摄取。在60分钟时在心脏中的摄取远低于用（R，S）-非对映异构体观察到的摄取。与未标记的（R，S）-FMeQNB共注射时的摄取抑制仅在心脏、丘脑和脑桥中显著。与未标记的（R，R）-FMeQNB共注射时的摄取抑制在所有脑区域中是相当均匀的。用（R）-QNB置换显示出更不同量的置换。这些结果与（R，R）- [18F]-FMeQNB在体内具有M1选择性一致。
We have developed a multistep radiochemical synthesis of two diastereomers of quinuclidinyl-4-[18F]-fluoromethylbenzilate ([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.