High yield and semi-automated synthesis procedure of (R)-[11C]PK11195

1900 Objectives: There has been a great deal of interest recently in applying (R)-[11C]PK11195 PET for neuropathologies involving neuroinflammation and activated microglia. In our hands, radiochemical yields of (R)-[11C]PK11195 using the reported KOH/DMSO method (Camsonne et al., 1984) were inconsistent. We report here a modified radiosynthesis procedure using NaH/DMSO (Hashimoto et al., 1989) that consistently produced the desired radioligand in high radiochemical yield and purity. Methods: A solution of (R)-N-Desmethyl-PK11195 (1.0-1.2 mg) in anhydrous DMSO (250 µL) was added to 3-4 mg of NaH (60% in oil) at room temperature 10 minutes before end-of-beam (EOB). [11C]Methyl iodide was slowly introduced into the precursor solution over 2-3 minutes and then the reaction vial was closed for 1 minute. After purging for 30 sec with a flow of argon, 0.8 mL of water was added to the reaction mixture. The resulting suspension was loaded onto an on-line C-18 extraction cartridge mounted on an HPLC injector valve. The cartridge was then washed with 10 mL of water or normal saline solution. The crude product, adsorbed onto the C-18 cartridge, was purified by semi-preparative HPLC (Luna, C-18, 5 µm, 250 x 10 mm) by directing the solvent flow (65% ethanol, 3 mL/min) through the cartridge. By monitoring the eluant with a flow-through radiation detector, the major portion (149 ± 22 mCi in 2.0 mL eluant) of the (R)-[11C]PK11195 fraction was collected (tR= 11 to 13 min) in a sterile vial containing 200 µL of Tween-80 (to minimize adsorption of the radioligand on the filter and plastic components). The resulting solution was then diluted with 10 – 11 mL of normal saline and sterilized by filtration (0.2µm nylon filter). Radiochemical and chemical purities of the product were determined by HPLC (Inertsil, C-8, 5 µm, 3.2 X 250 mm) with 10 mM KH2PO4/acetonitrile, 35/65, as the eluant, employing both radioactive (NaI scintillation) and ultraviolet (300 nm) detection. With a flow rate of 1.0 mL/min, (R)-[11C]PK11195 elutes in 4.9 min. The elution time of the potential dechlorinated radiochemical impurity (Cleij et al., 2003) was 4.6 min. Results: The radiochemical yield of the formulated (R)-[11C]PK11195 (collected portion; 75 – 80% of total product produced) was 37.9 ± 4.8% (EOB, n=17). Uncorrected radiochemical yield was 12.3 ± 1.7% (based on 11CO2) with a total synthesis time of 39 minutes (EOB). Specific activity was 994 ± 131 Ci/mmol (EOS). Radiochemical and chemical purities were >98%. Conclusions: We have developed a reliable semi-automated radiosynthesis procedure which produces (R)-[11C]PK11195 in high radiochemical yield and purity.