Knol Remco J J, van den Bos Jan C, Janssen Anton G M, de Bruin Kora, van Eck-Smit Berthe L F, Booij Jan
Department of Nuclear Medicine, Medical Center Alkmaar, Wilhelminalaan 12, 1815 JD Alkmaar, The Netherlands.
Int J Mol Imaging. 2011;2011:709416. doi: 10.1155/2011/709416. Epub 2011 Jun 13.
Disturbances of the cerebral cholinergic neurotransmitter system are present in neurodegenerative disorders. SPECT or PET imaging, using radiotracers that selectively target muscarinic receptor subtypes, may be of value for in vivo evaluation of such conditions. 6β-acetoxynortropane, a potent muscarinic M(2) receptor agonist, has previously demonstrated nanomolar affinity and high selectivity for this receptor. Based on this compound we synthesized four nortropane derivatives that are potentially suitable for SPECT imaging of the M(2) receptor. 6β-acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M(1-3) receptors. The original 6β-acetoxynortropane displayed high affinity (K(i) = 70-90 nM) to M(2) receptors and showed good selectivity ratios to the M(1) (65-fold ratio) and the M(3) (70-fold ratio) receptors. All new derivatives showed reduced affinity to the M(2) subtype and loss of subtype selectivity. It is therefore concluded that the newly synthesized derivatives are not suitable for human SPECT imaging of M(2) receptors.
神经退行性疾病中存在大脑胆碱能神经递质系统紊乱。使用选择性靶向毒蕈碱受体亚型的放射性示踪剂进行单光子发射计算机断层扫描（SPECT）或正电子发射断层扫描（PET）成像，可能对这类疾病的体内评估有价值。6β-乙酰氧基去甲托烷是一种强效毒蕈碱M(2)受体激动剂，此前已证明其对该受体具有纳摩尔亲和力和高选择性。基于该化合物，我们合成了四种可能适用于M(2)受体SPECT成像的去甲托烷衍生物。对6β-乙酰氧基去甲托烷和新型衍生物进行了体外试验，检测它们对毒蕈碱M(1-3)受体的亲和力。原始的6β-乙酰氧基去甲托烷对M(2)受体显示出高亲和力（K(i)=70-90 nM），对M(1)受体（65倍比值）和M(3)受体（70倍比值）显示出良好的选择性比值。所有新衍生物对M(2)亚型的亲和力均降低，且亚型选择性丧失。因此得出结论，新合成的衍生物不适用于人类M(2)受体的SPECT成像。
