Synthesis and evaluation of fluorinated derivatives of fentanyl as candidates for opiate receptor studies using positron emission tomograpry

Three fluorinated derivatives of fentanyl, fluorofentanyl (3), keto‐fluorofentanyl (5), and fluorofentanol (6), were synthesized and their abilities to compete with ³H‐diprenorphine for binding sites in guinea pig brain membranes were determined. The relative potencies were fentanyl > 3 ∼ 6 ≫ 5. On the basis of its apparent affinity for opiate receptors and its relative ease of synthesis,.6 was selected for further study. Fentanyl was slightly better than.6. in its ability to compete with [³H]naltrexone for binding sites in rat brain membranes. Both fentanyl and 6 exhibited a similar high “sodium ratio” (quotient of the IC₅₀'s against [³H]naltrexone in the presence and absence of sodium chloride) generally characteristic of opiate agonists. The analgesic potencies of fentanyl and 6 were determined in rats by measuring suppression of locomotion and vocalization responses to footshock. 6 appeared slightly less potent than fentanyl, but produced a similar analgesia and catalepsy which was entirely blocked by pretreatment of rats with naloxone, an opiate antagonist. A rapid synthesis of [¹⁸F]‐6 was developed and the tissue distribution of [¹⁸F]‐6 in mice was determined 5, 60, and 120 minutes after intravenous injection. The use of this general route to ¹⁸F‐labeled derivatives of fentanyl for studies of the opiate receptor using positron emission tomography is planned.