[ C]Carfentanil PET Whole-Body Imaging of Mu-Opioid Receptors: A First In-Human Study.

INTRODUCTION

Mu-opioid receptors (MORs) are G-coupled protein receptors with a high affinity for both endogenous and exogenous opioids. MORs are widely expressed in the central nervous system (CNS), peripheral organs, and the immune system. They mediate pain and reward and have been implicated in the pathophysiology of opioid, cocaine, and other substance use disorders. Using the long axial field-of-view (LAFOV) PennPET Explorer instrument and the MOR selective radioligand [ C]carfentanil ([ C]CFN), we measured the distribution of MORs in 13 healthy humans. We also examined sex differences in MOR distribution at baseline and after pretreatment with the MOR antagonist naloxone.

METHODS

Six female and seven male healthy subjects underwent two [ C]CFN PET imaging sessions-one at baseline and one immediately following pre-treatment with the MOR antagonist naloxone (13 mcg/kg). Whole-body PET imaging was performed on the PennPET Explorer, a 142-cm axial bore instrument. [ C]CFN brain distribution volume ratios (DVRs) were determined using the occipital cortex and the visual cortex within it as reference regions. For peripheral organ DVRs, the descending aorta and proximal extremity muscle (biceps/triceps) were used as reference regions.

RESULTS

Naloxone blockade reduced MOR availability by 40-50% in the caudate, putamen, thalamus, amygdala, and ventral tegmentum, brain regions known to express high levels of MORs. Women showed greater receptor occupancy in the thalamus, amygdala, hippocampus and frontal and temporal lobes and a greater naloxone-induced reduction in thalamic MOR availability than men (p's <0.05). For determining brain MOR availability, there was less variance in the visual cortex than the occipital cortex reference region. For peripheral MOR determination, the descending aorta reference region showed less variance than the extremity muscle, but both showed blocking effects of naloxone.

CONCLUSIONS

[ C]CFN whole- body PET scans are useful for understanding MOR physiology under both baseline and blocking conditions. Extra-CNS reference regions may be useful for quantifying radiotracers when a region devoid of binding in the CNS is unavailable. The LAFOV PET instrument was useful for measuring changes in the short-lived radiotracer [ C]CFN, with and without naloxone blocking. Further research is needed to evaluate the behavioral and clinical relevance of sex differences in naloxone-MOR interactions.