Synthesis and Characterization of a New Carbon-11 Labeled Positron Emission Tomography Radiotracer for Orexin 2 Receptors Neuroimaging

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 (EC₅₀ on OX₂R: 0.023 μM, Ki on hOX₂R: 0.14 μM). Synthesized and characterized as an OX₂R PET probe, [¹¹C]MDK-5220 was evaluated for its potential as a tracer. Biodistribution studies in mice were conducted to assess OX₂R binding selectivity, with particular attention to its interaction with P-glycoprotein (P-gp) on the blood-brain barrier.

Results

[¹¹C]MDK-5220 exhibited promising attributes as an OX₂R PET probe, demonstrating robust OX₂R binding selectivity in biodistribution studies. However, an observed interaction with P-gp impacted its brain uptake. Despite this limitation, [¹¹C]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 [¹¹C]MDK-5220 as an OX₂R 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

[¹¹C]MDK-5220 emerges as a promising OX₂R 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.

Keywords:

• synthesis and characterization
• orexin-2 receptor
• positron emission tomography
• carbon-11 labeling
• neuroimaging

Acknowledgments

The National Institute of Health DA048123 supported this research. The imaging studies were performed at the Athinoula A. Martinos Center for Biomedical Imaging of the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Regional Resource supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. This work also involved using instruments supported by the NIH Shared Instrument Grant Program and/or High-End Instrument Grant Program; extraordinary grant numbers: S10RR017208, S10RR026666, S10RR022976, S10RR019933, S10RR023401. The authors are thankful to the Martinos Center radiopharmacy and imaging staff for the help with rodent experiments and radioisotope production.

Disclosure

The authors report no conflicts of interest in this work.