The MCH receptor 1 (MCHr1) is a peptide receptor associated with caloric intake. It is located in the hypothalamic region of the brain and has been extensively investigated as a target for weight management. As a part of our internal drug discovery program culminating in the discovery of AZD1979, extensive efforts were made to discover a PET ligand for the MCHr1 for assessment of target engagement in the clinic. For only a minority of the CNS targets investigated a PET ligand is available and for MCHr1 this is extremely challenging. The MCH receptor 1 has a low expression in the brain and known MCHr1 antagonists possess far from ideal properties to be useful as PET ligands. Our work focused on the AstraZeneca chemical series and a screening cascade was set up to identify the most promising compounds with a focus on unbound fraction in the brain and potency. The presentation will show the outcome of this work and subsequent PET studies on potential candidate ligands. We will also disclose PET microdosing studies with 11C-labelled AZD1979 in Rhesus monkeys confirming a 1:1 free brain to plasma ratio.

Assessment of MCHr1 target engagement in the brain using PET imaging

253rd National Meeting (2017)

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