Project 3: CRF1 recoptor PET Ligand Development

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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.