Fully automated high yield synthesis of (R)‐ and (S)‐[¹¹C]verapamil for measuring P‐glycoprotein function with positron emission tomography

Racemic (±) verapamil is a well characterized substrate for P‐glycoprotein (P‐gp). However, the in vivo pharmacokinetics and pharmacodynamics of both enantiomers are reported to be different. In the preparation of evaluation studies of both enantiomers in animals and humans, the purpose of the present study was to optimize and automate the synthesis of ( R )‐ and ( S )‐[ 11 C]verapamil. ( R )‐ and ( S )‐[ 11 C]verapamil were prepared from ( R )‐ and ( S )‐desmethyl‐verapamil, respectively, by methylation with no‐carrier added [ 11 C]methyliodide or [ 11 C]methyltriflate. Different conditions of the methylation reaction were studied: reaction time, temperature, base and solvent, and chemical form of the precursor using either the hydrochloric acid salt or the free base of the starting material. After optimization, the synthesis was fully automated using home‐made modules and performed according to GMP guidelines. Optimal yields of 60–70% for the methylation reaction were obtained using 1.5 mg of the free base of ( R )‐ or ( S )‐desmethyl‐verapamil in 0.5 ml of acetonitrile at 50°C for 5 min with [ 11 C]methyltriflate as methylating agent. Under the same reaction conditions, but with a reaction temperature of 100°C, the radiochemical yield starting with [ 11 C]methyliodide as methylation reagent was 40%. The specific activity of ( R )‐ and ( S )‐[ 11 C]verapamil was >20 GBq/μmol and the radiochemical purity was >99% for both methods. The total synthesis time was 45 min. The automated high yield synthesis of ( R )‐ and ( S )‐[ 11 C]verapamil provides the means for evaluating both enantiomers as in vivo tracers of P‐gp function.