Corticotropin-releasing hormone (CRH) is a neuropeptide, which regulates endocrine and autonomic responses to stress through G-protein coupled receptors, CRHR1 or CRHR2. A radiolabeled ligand which is useful for monitoring changes in vivo in CRF1 receptor occupancy would be of a great help in understanding the course and pathophysiology of stress-related diseases as well as in the clinical development of non-peptide antagonist drug candidates.
We have developed a high-affinity CRHR1 antagonist, BMK-I-152 and continued our efforts in developing radioligands based upon BMK-I-152 capable of in vivo PET imaging CRHR1 in the brain. The radiolabelling process of the BMK-I-152 at both the 3 and 4 position with [76Br] were carried out and the PET imaging studies on both compounds have been studied. The result of in vitro autoradiography studies reveals that both 4-[76Br]BMK-152 and 3-[76Br]BMK-152 were found selective for CRF1 receptors, however, only 4-[76Br] isomer displayed subnanomolar affinity binding, and the 4-[76Br] isomer had approximately 70-fold higher affinity than that of the 3-[76Br] isomer. Ex vivo autoradiography studies of rat brain uptakes of 4-[76Br]BMK-152 showed regional localization which is consistent with the known CRF1 receptor distribution and this study confirmed that BMK-I-152 had a potential as an excellent PET ligand for in vivo imaging of CRF1 receptors.