Synthesis of high specific activity [¹⁸F]-fluoroethyl -tosylate, -spiperone, and -diprenorphine

Objectives [¹⁸F]fluoroethyltosylate(FET) is often made from ethylene ditosylate to prepare radiopharmaceuticals via fluoroethylation. Production of [¹⁸F]fluoroethylspiperone (FES) and [¹⁸F]fluoroethyldiprenorphine (FEDPN) from FET, using commercial ditosylate, gave products with low measured specific activities [7-40 MBq ( 0.2-1 Ci)/μmol]. Similar specific activities are reported in fluoroethylation literature. Commercial ditosylate contained an impurity (< 7%, likely chloroethyl tosylate) that co-eluted with FET. It reacted with precursors to give byproducts that coeluted with the desired products, drastically reducing effective specific activities. The goal of the work was to eliminate the impurity to increase effective specific activities and yields.

Methods Ditosylate was recrystallized from chloroform and/or ethyl acetate. The preferred method was precipitation from acetonitrile with 1:1 methanol:water. Commercial and purified samples were analyzed by HPLC and used in radiolabeling of FET for production of FES and FEDPN to measure effective specific activity of final products.

Results Recrystallization reduced (< 1%) but did not eliminate the impurity, though chloroform recrystallization could increase it. Impurity could not be detected after precipitation. With purification, the chemical yield of FET increased from 45% to 90%. FET was used to synthesize FES (85% yield and specific activity of [3.5-4.8 Tbq (95-130 Ci) μmol] at EOS) and FEDPN ( 30% yield and specific activity of [4 Tbq (100 Ci)/μmol] at EOS.

Conclusions A small amount of an impurity in commercial ethylene ditosylate co-elutes with FET, reducing yield and effective specific activity. Crystallization, though traditional, is inadequate to remove it. The purification method reported here completely eliminates this impurity. Use of analytically pure ditosylate resulted in a significant increase in radiolabeling yield, and drastic improvement in specific activity [4 Tbq (100 Ci)/μmol] of synthesized radiopharmaceuticals