PET imaging of the opioid system using radioligands: Synthetic approaches and translational applications

Opioid receptors (ORs) are members of the G-protein coupled receptor (GPCR) superfamily and are classified into three primary subtypes: mu (MOR), delta (DOR), and kappa (KOR), in addition to the more recently identified opioid receptor-like 1 (ORL-1) subtype. The elucidation of high-resolution crystallographic structures of all opioid receptor subtypes has substantially advanced the rational design and development of opioid-based therapeutics, which are widely employed in the treatment of pain, substance use disorders, addiction, and mood disorders. The opioid system has also been investigated through Positron Emission Tomography, a powerful imaging modality that enables both qualitative and quantitative evaluation of opioid receptor-mediated signalling in the central and peripheral nervous system. Over the past decades, several radioligands with high affinity and selectivity for opioid receptors have been successfully developed for use in preclinical and clinical research. This review provides a comprehensive overview of the main synthetic approaches utilized for the development of opioid receptor radioligands. In addition, the preclinical and clinical applications of the most widely characterized opioid radioligands are critically discussed.