IMPROVED SYNTHESIS OF N-SUCCINIMIDYL 4-[F-18]FLUOROBENZOATE AND ITS APPLICATION TO THE LABELING OF A MONOCLONAL-ANTIBODY FRAGMENT

Our previously reported method for the F-18 labeling of antibodies using N-succinimidyl 4-[N-18]-fluorobenzoate (SFB) involved a rather long synthesis time. Here we present an improved method for the synthesis of SFB which reduces the synthesis time by about 45 min. A reaction time of 5-8 min (versus 25 min for the original procedure) was sufficient in the fluorination step to form 4-[F-18]-fluorobenzaldehyde in high yield. In the original method, 30-35 min was necessary to convert 4-[F-18]-fluorobenzoic acid to SFB using dicyclohexylcarbodiimide and N-hydroxysuccinimide. When N,N-disuccinimidyl carbonate was used, facile conversion of 4-fluorobenzoic acid to SFB was seen at a micromolar level. At a tracer level, no product was formed at room temperature; however, complete consumption of starting material was observed. Heating at 150-degrees-C resulted in the formation of SFB in more than 80 % yield in 1-3 min. HPLC purification of SFB was necessary since use of crude SFB, or SFB purified using a silica solid-phase cartridge column, resulted in lower protein coupling yields. Furthermore, use of crude SFB resulted in cross-linking and lower immunoreactivity of antibody. Largely as a result of the considerable reduction in total labeling time, these modifications have increased the amount of F-18-labeled antibody available per 100 mCi of [F-18]fluoride by 30-35%.