[¹¹C]Fentanyl: Radiosynthesis and Preclinical PET Imaging for Its Pharmacokinetics

Fentanyl is a potent synthetic opioid widely used for pain management and anesthesia, but the high prevalence of its misuse and its key contribution to overdose fatalities in the United States have made it a major drug of concern. Although fentanyl's onset, duration, and toxicity depend on its pharmacokinetics and specific tissue distribution, most studies have focused primarily on plasma concentrations, leaving its distribution in critical tissues largely unexplored (this knowledge gap limits our understanding of fentanyl's clinical effects, tissue accumulation, and the factors influencing its efficacy and safety). Here, we report the radiosynthesis of [¹¹C]fentanyl for PET imaging and present a preliminary whole-body pharmacokinetic study in rodents.

[¹¹C]Fentanyl was synthesized in 42 mins in a high radiochemical yield (10.4 ± 5.7%, n = 5), radiochemical purity (> 99%), and molar activity (up to 2571.5 GBq/μmol at EOB). N,N-diisopropylethylamine in chloroform was optimal for amidation. PET imaging in rats revealed rapid brain uptake (SUV_max 2.71 ± 1.04 g/mL) and fast washout (T_1/2 = 5.06 min), both significantly increased by efflux transporter inhibition or knockout. Peripherally, high and prolonged uptake in adipose tissues was observed (SUV_max = 1.73 ± 0.313 g/mL, T_1/2 = 177 min), with > 60% of C-11 remaining as unchanged [¹¹C]fentanyl at 60 min.

We successfully developed and automated the radiosynthesis of [¹¹C]fentanyl, enabling PET imaging that revealed rapid brain kinetics and a critical role of P-gp/BCRP efflux in fentanyl disposition in brain. Prolonged retention in adipose tissue may delay brain clearance, potentially increasing the risk of renarcotization (as has been reported in clinical cases after naloxone reversal). These findings advance our ability to quantify fentanyl tissue distribution and pharmacokinetics in the brain and body and provide a valuable tool for further studies in preclinical and clinical settings.