7-甲基-2-外型-(3'-碘-5'-吡啶基)-7-氮杂双环[2.2.1]庚烷对映体的新合成及评价：作为烟碱型乙酰胆碱受体PET成像的立体选择性配体
New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors.
作者信息
Gao Yongjun, Horti Andrew G, Kuwabara Hiroto, Ravert Hayden T, Holt Daniel P, Kumar Anil, Alexander Mohab, Wong Dean F, Dannals Robert F
机构信息
Division of Nuclear Medicine, Department of Radiology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-0816, USA.
出版信息
Bioorg Med Chem Lett. 2008 Dec 1;18(23):6168-70. doi: 10.1016/j.bmcl.2008.10.012. Epub 2008 Oct 7.
A simple and efficient synthesis of nAChR antagonist (+/-)-7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((+/-)-NMI-EPB) has been developed. Both enantiomers of (+/-)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, K(i)=2310, 1680 pM; (-)-NMI-EPB, K(i)=55, 68 pM). The enantiomers were stereoselectively radiolabeled with (11)C. In the distribution studies in the rodent brain (11)C-NMI-EPB specifically labeled nAChR whereas (11)C-NMI-EPB exhibited little specific binding. In the baboon PET study (11)C-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.
已开发出一种简单有效的合成烟碱型乙酰胆碱受体拮抗剂（±）-7-甲基-2-外向-（3'-碘-5'-吡啶基）-7-氮杂双环[2.2.1]庚烷（（±）-NMI-EPB）的方法。通过半制备手性高效液相色谱法分离了（±）-NMI-EPB的两种对映体。这些对映体在抑制结合亲和力方面表现出显著差异（（+）-NMI-EPB，K（i）=2310、1680 pM；（-）-NMI-EPB，K（i）=55、68 pM）。这些对映体用（11）C进行了立体选择性放射性标记。在啮齿动物脑部分布研究中，[（11）C]（-）-NMI-EPB特异性标记烟碱型乙酰胆碱受体，而[（11）C]（+）-NMI-EPB几乎没有特异性结合。在狒狒正电子发射断层扫描研究中，[（11）C]（-）-NMI-EPB在注射后90分钟内未达到稳态，这表明该放射性配体在定量成像方面可能存在一些局限性。
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