Project 3: CRF1 recoptor PET Ligand Development

这个修订项目的前提仍然是开发针对大脑 CRF 的药物-\ 受体依赖于新型、经过验证的 CRFi 受体 PET 配体的可用性。配套 这种配体的应用包括测试作用机制假设，其中剂量和时间效应 候选CRF^受体拮抗剂的关系由占位百分比定义 脑CRF，受体。与治疗和副作用相关的剂量探索研究作为百分比的函数 将启用并指导第二阶段试验。评估是否患有重度抑郁或焦虑 疾病或 CRF 受体基因变异与体内脑 CRF^ 受体改变有关 可用性代表了应用此类 PET 配体测试病理生理学模型的示例 分别是药物遗传学。我们建议以 CRF 的持续努力为基础！受体PET 配体开发计划的资助作为当前 U19 奖项的补充。修订后的项目 3 仍然存在 作为分子设计、化学以及基于体外和体内候选物评估的迭代计划 两种不同但平行的方法从常见的吡啶并吡嗪酮CRF-1受体拮抗剂开始。 所提出的方法代表了吡啶并吡嗪酮起始分子的计划修饰，以及 操纵面外芳环对 CRF1 受体结合影响的具体表征 亲和力。提出了五个具体目标来产生 11C 和 18F 标记的大脑 CRF^ 受体 PET 配体是由化学合成的拟议程序和逐步的相互作用产生的 候选 CRFi 受体 PET 配体的评估。候选人评估将包括 9 个步骤 分层模型，具有明确定义的标准作为跨越转染细胞系统、啮齿动物、 以及非人类灵长类动物的体外和体内评估，以优化 CRFi 的靶配体特性 受体亲和力、亲脂性和代谢稳定性。不断发展的结构-活动关系 (SAP) 数据将 完善合成化学方案以产生重新进入评估方案的新候选物， 并将与 QSAR 分子建模/药物合作开发分子建模方法 埃默里化学/药理学联合倡议的发现计划。末期候选人评估 将涉及猴子体内 microPET 成像，以建立定量的可行性和模型 脑发射数据、剂量和时间依赖性脑 CRF 的评估、GSK-008 的受体占用率、 和器官剂量测定。支持人类使用 IND 申请的测试的最后阶段是 通过本合作协议中的 GSK 合作伙伴关系实现。该拟议项目 3 的目标是 表征 GSK-008 与灵长类大脑 CRF^ 受体的相互作用，并提供有价值的 CRF 研究领域新颖、有效的 PET 配体。

The premise of this revised project remains that the development of medications targeting the brain CRF-\ receptor is dependent on the availability of a novel, validated CRFi receptor PET ligand. Supporting applications of such a ligand include testing mechanism of action hypotheses in which the dose- and timeeffect relationships of candidate CRF^ receptor antagonists are defined by the percent occupancy of the brain CRF, receptor. Dose finding studies related to therapeutic and side effects as a function of percent occupancy would be enabled and guide Phase II trials. Assessing whether major depression or anxiety disorders, or CRF, receptor gene variation, are associated with altered in vivo brain CRF^ receptor availability represent examples of the application of such a PET ligand to test models of pathophysiology and pharmacogenetics, respectively. We propose to build on the ongoing efforts of the CRF! receptor PET ligand development initiative funded as a supplement to the current U19 award. Revised Project 3 remains as an iterative plan of molecular design, chemistry, and in vitro and in vivo candidate evaluation based on two distinct but paralleling approaches starting from common pyridopyrazinone CRF-\ receptor antagonists. Proposed approaches represent planned modifications of the pyridopyrazinone starting molecule, and the specific characterization of the effect of manipulating the out-of-plane aryl ring on CRF1 receptor binding affinity. Five specific aims are proposed to yield 11C- and 18F-labeled versions of brain CRF^ receptor PET ligands resulting from the interactions between a proposed program of chemical synthesis and the step-wise evaluation of candidate CRFi receptor PET ligands. Candidate evaluation would involve a 9-step hierarchical model with well-defined criteria as branch points that spans transfected cell systems, rodents, and in vitro and in vivo assessments in non-human primates to optimize the target ligand properties of CRFi receptor affinity, lipophilicity and metabolic stability. Evolving structure-activity relationship (SAP) data would refine synthetic chemistry schemes to generate novel candidates for re-entry into the evaluation scheme, and would evolve a molecular modeling approach in collaboration with the QSAR molecular modeling/drug discovery program of the joint Chemistry/Pharmacology Emory initiative. End stage candidate evaluation would involve in vivo microPET imaging in monkeys to establish the feasibility and models for quantitating brain emission data, evaluation of dose-and time-dependent brain CRF, receptor occupancy for GSK-008, and organ dosimetry. The final stage of testing in support of an IND application for human use would be enabled by the GSK partnership in this cooperative agreement. The goals of this proposed project 3 are to characterize the interactions of GSK-008 with the primate brain CRF^ receptor, and to provide a valuable novel, valid PET ligand to the field of CRF research.