Background: In 2022, the United States reported 107,941 drug overdose deaths, corresponding to an age-adjusted mortality rate of 32.6 per 100,000 population. While fentanyl remains a potent analgesic in medical practice, it is also a significant factor in cases of opioid use and overdoses nationwide. Despite the widespread use and misuse of fentanyl, there is no in vivo imaging probe for pharmacokinetics research. Herein, we synthesized [¹¹C]fentanyl and report its preliminary brain study in rodents using positron emission tomography (PET).
Methods: [¹¹C]fentanyl was synthesized in two steps: 1) preparation of [¹¹C]propionyl chloride, 2) amidation of 4-anilino-N-phenethylpiperidine (4-ANPP). [¹¹C]propionyl chloride was prepared using an "in-loop" method for [¹¹C]carboxylation, where [¹¹C]CO₂ in a stream of helium was reacted with ethylmagnesium bromide. Phthaloyl chloride was then used as a chlorinating agent to produce [¹¹C]propionyl chloride, which was subsequently purified by distillation. Various tertiary amines and solvents were tested for rapid amidation in the radiosynthesis of [¹¹C]fentanyl.
Results: The total synthesis time from the end of bombardment (EOB) was approximately 42 minutes, achieving high radiochemical purity (>99%), decay-corrected radiochemical yield of 10.4 ± 5.7% (n = 5), and high specific activity (44.7 ± 22.1 Ci/μmol, n = 5) at EOB. Diisopropylethylamine in chloroform provided the highest radiochemical yield for the [¹¹C]amidation step (62.5 ± 11.2%, n = 3). Baseline PET imaging revealed that IV [¹¹C]fentanyl exhibited rapid brain uptake followed by fast clearance, with a maximum standardized uptake value (SUV_max) of 2.71, a time to reach maximum uptake (T_max) of 1.7 minutes, and a half-life (T_1/2) of 4.7 minutes (n = 3).
Conclusion: 2-step radiosynthesis was optimized to provide a [¹¹C]fentanyl production method showing high specific activity and radiochemical purity. PET study for fentanyl’s pharmacokinetics is under way in rodents and non-human primates.

WooChan Kim

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