A positron emission tomography (PET) tracer for orexin receptors (OXRs) is of potential utility for assessing levels of these receptors in neuropsychiatric conditions, and for quantifying receptor occupancy by a candidate therapeutic drug, serving to link pharmacodynamics and pharmacokinetics of the drug toward estimation of its optimal dosage. However, no radiotracer is currently available for an in vivo PET assay of OXRs. The aim of this study is to establish a systematic strategy for developing a novel PET tracer for OXR type 2 (OX2R). Novel classes of cyclopropane derivatives were identified as potent OX2R ligands, and were subsequently screened for PET tracer candidates, based on their in vitro inhibitory constants for OX2R, 11C labelability and lipophilicity suitable for entry into the brain. The selected compounds were radiolabeled with 11C, and their performance was evaluated by in vitro autoradiographic and in vivo PET imaging of animal brains. These assessments have enabled us to find a new radioligand with potential as a lead for practical imaging agents, and to further determine properties of compounds, including ranges of affinity for OX2R and flux ratio for efflux transporters, required for high-contrast PET.

Synthesis and evaluation of novel radioligands for positron emission tomography imaging of central orexin-2 receptor

248th National Meeting (2014)

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