Radioligands for Sigma-2 Receptor Studies in the CNS by PET

 描述（由申请人提供）：sigma-2（s2）受体在焦虑、抑郁、运动障碍和精神兴奋剂滥用中发挥作用。其CNS药理学的这些重要方面仍然相对未探索。在某种程度上，这是由于缺乏用于动物模型中s2受体的体内研究和用于非侵入性脑PET成像的放射性配体的结果。因此，NIH CNS放射性示踪剂表列出C-11 SA 4503是PET可用的s1受体探针，而未列出s2受体探针，这并不奇怪。我们最近报道，可卡因的运动刺激作用在小鼠中被衰减的高度s2受体选择性四氢异喹啉苯甲酰胺管理。由于没有合适的放射性配体，我们不能证明可卡因与脑内s2受体在体内的直接相互作用。我们的中心假设是，可以开发新的放射性配体，将显示高的S2受体的亲和力和选择性，并将成为脑PET成像的S2受体的主要候选人。一个系统的药物放射化学方法，已作为一个成功的范例，为其他PET成像放射性示踪剂的发展，作为我们的建议的框架。我们的具体目标是：1）在正常小鼠体内评价[18F]-标记的s2受体配体的药代动力学、药理学、代谢稳定性和PET成像潜力，和2）制备以高亲和力和选择性结合s2受体的新型[18F]-标记的配体。该提案的具体创新来自对关键化学结构修饰的认识，当这些化学结构修饰结合成新分子时，应导致优化的放射性配体。本提案是针对PAR-13-282：“PET和SPECT成像配体作为药物发现和CNS疾病病理生理学研究的生物标志物的开发和应用（R21）”提交的。“在R21资助期结束时，我们完全预计一种或多种[18 F]标记的放射性配体将表现出高的s2受体亲和力和选择性、体内已证实的特异性结合、适当的药代动力学、良好的代谢稳定性以及微型PET脑成像的实用性。这种放射性配体的开发将为CNS中s2受体介导的活性的鉴别提供新的和独特的机会，并促进s2受体配体作为CNS疾病的治疗剂的开发。此外，脑PET的最佳S2受体配体在肿瘤学领域也可能具有很大的实用性。

 DESCRIPTION (provided by applicant): The sigma-2 (s2) receptors play a role in anxiety, depression, movement disorders and psychostimulant abuse. These important aspects of their CNS pharmacology remain relatively unexplored. In part, this is a consequence of the lack of radioligands for in vivo studies of s2 receptors in animal models and for non- invasive brain PET imaging. Thus, it is not surprising that the NIH CNS Radiotracer Table lists C-11 SA4503 is an available s1 receptor probe for PET, while none are listed for the s2 receptor. We recently reported that cocaine's locomotor stimulatory effects in mice are attenuated by administration of a highly s2 receptor-selective tetrahydroisoquinolinyl benzamide. We could not demonstrate a direct interaction of cocaine with s2 receptors in vivo in brain because there are no appropriate radioligands. Our central hypothesis is that novel radioligands can be developed that will display high s2 receptor affinity and selectivity, and will emerge as leading candidates for brain PET imaging of s2 receptors. A systematic medicinal radiochemistry approach that has served as a successful paradigm for the development of other PET imaging radiotracers serves as the framework for our proposal. Our specific aims are: 1) the evaluation of the pharmacokinetics, pharmacology, metabolic stability and PET imaging potential of [18F]-labeled s2 receptor ligands in vivo in normal mouse and 2) the preparation of novel [18F]-labeled ligands that bind with high affinity and selectivity to s2 receptors. The specific innovation in this proposal derive from recognition of key chemical structural modifications that, when combined into new molecules, should lead to optimized radioligands. This proposal is submitted in response to PAR-13-282: "Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorders (R21)." At the end of the R21 funding period, we fully anticipate that one or more of the [18F]-labeled radioligands will display high s2 receptor affinity and selectivity, proven specific binding in viv, appropriate pharmacokinetics, good metabolic stability, and utility for micro-PET brain imaging. The development of such radioligands will provide new and unique opportunities for the discrimination of s2 receptor-mediated activities in the CNS, and facilitate the development of s2 receptor ligands as therapeutics for CNS disorders. Furthermore, optimal s2 receptor ligands for brain PET might also have great utility in the oncology realm.