Abstract
PURPOSE: Orexin receptors (OXRs) play a crucial role in modulating various physiological and neuropsychiatric functions within the central nervous system (CNS). Despite their significance, the precise role of OXRs in the brain remains elusive. Positron emission tomography (PET) imaging is instrumental in unraveling CNS functions, and the development of specific PET tracers for OXRs is a current research focus. METHODS: The study investigated MDK-5220, an OX2R-selective agonist with promising binding properties (EC(50) on OX(2)R: 0.023 μM, Ki on hOX(2)R: 0.14 μM). Synthesized and characterized as an OX(2)R PET probe, [(11)C]MDK-5220 was evaluated for its potential as a tracer. Biodistribution studies in mice were conducted to assess OX(2)R binding selectivity, with particular attention to its interaction with P-glycoprotein (P-gp) on the blood-brain barrier. RESULTS: [(11)C]MDK-5220 exhibited promising attributes as an OX(2)R PET probe, demonstrating robust OX(2)R binding selectivity in biodistribution studies. However, an observed interaction with P-gp impacted its brain uptake. Despite this limitation, [(11)C]MDK-5220 presents itself as a potential candidate for further development. DISCUSSION: The study provides insights into the functionality of the OX system and the potential of [(11)C]MDK-5220 as an OX(2)R PET probe. The observed interaction with P-gp highlights a consideration for future modifications to enhance brain uptake. The findings pave the way for innovative tracer development and propel ongoing research on OX systems, contributing to a deeper understanding of their role in the CNS. CONCLUSION: [(11)C]MDK-5220 emerges as a promising OX(2)R PET probe, despite challenges related to P-gp interaction. This study lays the foundation for further exploration and development of PET probes targeting OXRs, opening avenues for advancing our understanding of OX system functionality within the brain.