Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan.
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; Department of Biofunction Imaging Analysis, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Bioorg Med Chem. 2019 Jun 1;27(11):2245-2252. doi: 10.1016/j.bmc.2019.04.030. Epub 2019 Apr 25.
We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([Tc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (Tc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (K = 0.55 nM). Through the radiosynthesis of [Tc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [Tc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [Tc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [Tc]CPTT-A-E to the brain, [Tc]CPTT-A-E met the basic requirements for nAChR imaging.
我们设计了（S）-（5-（氮杂环丁烷-2-基甲氧基）吡啶-3-基）甲基环戊二烯三羰基锝羧酸酯（[Tc]CPTT-A-E），该化合物对烟碱型乙酰胆碱受体（nAChRs）具有高亲和力，使用（2（S）-氮杂环丁烷-2-基甲氧基）-吡啶（A-85380）作为先导化合物，开发了一种锝-99m-环戊二烯三羰基-锝（Tc）标记的 nAChR 成像探针。由于锝不含稳定同位素，因此通过配位与锝具有相同配位结构的同系元素铼合成了环戊二烯三羰基铼（CPTR）。进一步评估了对 nAChR 的结合亲和力。CPTR-A-E 对 nAChR 具有高结合亲和力（K=0.55 nM）。通过[Tc]CPTT-A-E 的放射性合成，可以获得放射性化学产率为 33%且放射性化学纯度大于 97%的目标化合物。脑的体外放射自显影研究表明，局部 nAChR 密度与每个感兴趣区域中积累的[Tc]CPTT-A-E 的量强烈相关。进一步的体内生物分布评估显示，与小脑（nAChR 密度低）相比，[Tc]CPTT-A-E 在丘脑（nAChR 密度高）中的积累更高。尽管需要进一步的研究来提高[Tc]CPTT-A-E 对大脑的摄取，但[Tc]CPTT-A-E 满足了 nAChR 成像的基本要求。
