An improved synthesis of dopamine D2/D3 receptor radioligands [11C]fallypride and [18F]fallypride

Improved syntheses of dopamine D2/D3 receptor radioligands [11C]Fallypride and [18F]Fallypride are reported. The phenolic precursor (9) for C-11 labeling and the Fallypride (10) reference standard were synthesized from the starting material 2-hydroxy-3-methoxy-5-(2-propenyl)benzoic acid methyl ester (1) in 7 and 8 steps with 16% and 5% overall chemical yields, respectively. The tosylated precursor (15) for F-18 labeling was synthesized from compound 1 in 5 steps with 32% overall chemical yield. An alternate synthetic approach for Fallypride has been developed using the same starting material 1 in 5 steps with 26% overall chemical yield. [11C]Fallypride ([11C]10) was prepared by O-[11C]methylation of the phenolic precursor with [11C]methyl triflate and purified with a semi-preparative HPLC method in 50–60% radiochemical yield, decay corrected to end of bombardment (EOB), based on [11C]CO2, and 370±185 GBq/μmol specific radioactivity at EOB. [18F]Fallypride ([18F]10) was prepared by nucleophilic substitution of the tosylated precursor with K[18F]F/Kryptofix 2.2.2 and HPLC combined with solid-phase extraction (SPE) purification in variable (up to 50%) decay corrected radiochemical yield from K[18F]F and 111–222 GBq/μmol specific activity at EOB.