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.
of proposed project 3 to public health lies in its role in the integrated U19 approach to the cooperative development of psychiatric medications. Specifically, attaining the target project goal of developing a novel, valid CRFi receptor PET ligand would critically aid the development of medications for common, disabling disorders of mood and anxiety that are based on the strong theoretical, but as yet unrealized, potential of brain CRF! receptor antagonists. More generally, the availability of such a PET ligand would provide a useful tool for noninvasive exploration of the role of CRF in the physiology and pathophysiology of human behavior.
|Kilts, Clint D; Kennedy, Ashley; Elton, Amanda L et al. (2014) Individual differences in attentional bias associated with cocaine dependence are related to varying engagement of neural processing networks. Neuropsychopharmacology 39:1135-47|
|Kaye, Joanna L; Dunlop, Boadie W; Iosifescu, Dan V et al. (2014) Cognition, functional capacity, and self-reported disability in women with posttraumatic stress disorder: examining the convergence of performance-based measures and self-reports. J Psychiatr Res 57:51-7|
|Dunlop, Boadie W; Rothbaum, Barbara O; Binder, Elisabeth B et al. (2014) Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial. Trials 15:240|
|Sink, K S; Chung, A; Ressler, K J et al. (2013) Anxiogenic effects of CGRP within the BNST may be mediated by CRF acting at BNST CRFR1 receptors. Behav Brain Res 243:286-93|
|Zoellner, Lori A; Rothbaum, Barbara O; Feeny, Norah C (2011) PTSD not an anxiety disorder? DSM committee proposal turns back the hands of time. Depress Anxiety 28:853-6|
|Sink, Kelly S; Walker, David L; Yang, Yong et al. (2011) Calcitonin gene-related peptide in the bed nucleus of the stria terminalis produces an anxiety-like pattern of behavior and increases neural activation in anxiety-related structures. J Neurosci 31:1802-10|
|Mathew, Sanjay J; Vythilingam, Meena; Murrough, James W et al. (2011) A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Eur Neuropsychopharmacol 21:221-9|
|Martin, Elizabeth I; Ressler, Kerry J; Binder, Elisabeth et al. (2010) The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Clin Lab Med 30:865-91|
|Binder, E B; Nemeroff, C B (2010) The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol Psychiatry 15:574-88|
|Martin, Elizabeth I; Ressler, Kerry J; Jasnow, Aaron M et al. (2010) A novel transgenic mouse for gene-targeting within cells that express corticotropin-releasing factor. Biol Psychiatry 67:1212-6|
Showing the most recent 10 out of 35 publications