Synthesis of [¹⁸F]fluoroalkyl esters of carfentanil

With the aim to develop and evaluate new ligands for depicting the μ-opioid receptor with positron emission tomography, the ¹⁸F- fluoroalkyl esters of carfentanil, 3-carboxy-(2-[¹⁸F]fluoroethyl) fentanyl, (2-[¹⁸F]fluoroethyl-carfentanil) and 3-carboxy-(3-[ ¹⁸F]fluoropropyl)fentanyl (3-[¹⁸F]fluoropropyl- carfentanil) were prepared by a two-step radiosynthesis. Reacting carfentanil carboxylate sodium salt, added 0.96 eqv. of tetrabutyl ammonium hydroxide (TBAH), with no-carrier-added (n.c.a.) 2-[¹⁸F]fluoroethyltosylate for 20 min at 150°C in dimethyl formamide (DMF) provided 2-[ ¹⁸F]fluoroethyl carfentanil in an isolated radiochemical yield (RCY) of 36 ± 8%, a specific activity (S_A) of 35 ± 5TBq/mmol (n = 4) within a synthesis time of ∼100min. Similarly, 3-[ ¹⁸F]fluoropropyl carfentanil could be obtained by reacting the carfentanil TBA/Na salt with 3-[¹⁸F]fluoropropyl iodide at 160°C in DMF (isolated RCY = 6 ± 2%; ∼100min, S_A = 27 ± 5 TBq/mmol, n = 4). The developed methods allow the production of the two ¹⁸F-labeled carfentanil derivatives in amounts and specific activities necessary and relevant for a detailed preclinical evaluation of these new potential μ-opioid receptor ligands in vitro and in animal models.