Project 3: CRF1 recoptor PET Ligand Development

这一修订项目的前提仍然是针对脑CRF的药物的开发- 受体依赖于一种新的、有效的cRFI受体PET配体的可用性。支座 这种配体的应用包括测试作用假说的机制，在这些假说中，剂量和时间效应 候选CRF^受体拮抗剂的关系由 脑CRF受体。与治疗和副作用有关的剂量发现研究作为百分比的函数 将启用入住率并指导第二阶段试验。评估严重的抑郁症或焦虑症 疾病，或CRF，受体基因变异，与体内脑CRF受体改变有关 可用性代表了这种PET配体应用于测试病理生理学模型和 分别是药物遗传学。我们建议在CRF不断努力的基础上再接再厉！受体PET 作为目前U19奖的补充而资助的配基发展倡议。修订后的项目3仍保留 作为分子设计、化学以及体外和体内候选评估的迭代计划，基于 两种不同但平行的方法始于常见的吡咯烷酮类CRF受体拮抗剂。 提议的方法代表了计划中的对吡喃齐酮起始分子的修饰，以及 操纵平面外芳环对CRF1受体结合影响的特异性表征 亲和力。提出了五个特定的目标来制备11C和18F标记的脑CRF受体PET 一种化学合成方案与一步法相互作用所产生的配体 候选cRFI受体PET配体的评价。候选人评估将包括9个步骤 以明确定义的标准作为分支点的分层模型跨越转基因细胞系统、啮齿类动物、 并在非人类灵长类动物中进行体外和体内评估，以优化cRFI的靶配体性质 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 改进合成化学方案以生成重新进入评估方案的新候选方案， 并将与QSAR分子建模/药物合作开发一种分子建模方法 联合化学/药理学埃默里倡议的发现计划。结束阶段候选人评估 将涉及猴子体内的microPET成像，以建立量化的可行性和模型 脑发射数据，剂量和时间依赖性脑CRF的评估，GSK-008受体占有率， 和器官剂量测定。支持供人类使用的IND应用程序的最后测试阶段将是 由葛兰素史克在本合作协议中的合作伙伴关系促成。这一拟议项目3的目标是 鉴定GSK-008与灵长类动物脑CRF受体的相互作用，并提供有价值的 新型、有效的PET配体进入慢性肾功能衰竭研究领域。

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.