Our studies in the role of stress in drug abuse have continued. We and others have shown that stress can play an important role in promoting drug self-administration and relapse to drug abuse. The corticotropin releasing hormone receptor (CRHR1) plays a central role in initiation of the response to stress. Our studies suggest that CRHR1 antagonists such as antalarmin may be useful in the treatment of human alcohol dependence and relapse to other drugs of abuse, and that optimal treatment may vary between different subtypes of patients. The development of a functional ligand for imaging CRH receptors with positron emission tomography is a difficult problem that has been unsuccessfully attempted by numerous research groups worldwide. The availability of such a PET ligand would enable many diverse studies of drug abuse and various psychiatric disorders. In our studies toward this goal, we have now designed and synthesized unlabeled bromine-containing BMK-1-152 and its positron emitting 76Br labeled counterpart. BMK-1-152 showed excellent affinity for CHRR1, 0.35 nM vs. 125I ovine-CRH, a ligand specific for CRHR1. The binding of BMK-1-152 was shown to be remarkably dependent on the position of the bromine atom. When the bromine present in BMK-1-152 was moved to an adjacent position on the aromatic ring the resulting compound lost about 70-fold affinity. In view of the very favorable lipophilicity of BMK-1-152 (ClogP = 2.6) and its excellent affinity, BMK-1-152 appears to be a promising candidate for development as a PET ligand for CRHR1 receptors.
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