Comparative study of 18F-FBEM-Cys39-exendin-4 versus 18F-FBEM-Cys40-exendin-4 in insulinoma imaging

339 Objectives Insulinoma is overexpressed by glucagon-like peptide-1 receptor (GLP-1R). 18F-FBEM-Cys40-exendin-4 has been prepared for insulinoma imaging. Serine at C-terminal was not important for biological activity of exendin-4. Modification of exendin-4 by replacing the serine residues (ser39) with cysteine (cys39) may have less impact on the binding affinity of the peptide to the receptor. In this study, a novel 18F labeled exendin-4 analog, 18F-FBEM-Cys39-exendin-4, was synthesized and compared with 18F-FBEM-Cys40-exendin-4 in insulinoma models. Methods 18F-FBEM was synthesized by coupling 18F-Fluorobenzoic acid (18F-FBA) with N-(2-aminoethyl) maleimide and the reaction conditions were optimized. Cys39/ Cys40-exendin-4 were then conjugated with 18F-FBEM to obtain 18F-FBEM-Cys39/ Cys40-exendin-4. The GLP-1R targeting potential and pharmacokinetic profile of the tracers were analyzed in INS-1 insulinoma and MDA-MB-435 breast tumor model. Results The radiolabeled yields of 18F-FBEM-Cys39-exendin-4 were 30.1±2.6% (based on 18F-FBEM, non-decay corrected). The radiochemical purity of 18F-FBEM-Cys39-exendin-4 is greater than 95% and the specific activity was at least 35GBq/μmol. The GLP-1R positive INS-1 insulinoma xenograft was clearly visible with good contrast to background, whereas, GLP-1R negative MDA-MB435 breast tumor was barely visible. Quantification of the PET data showed that the INS-1 tumor uptakes of 18F-FBEM-Cys39-exendin-4 were determined to be 10.01±1.21 ID/g at 60 min p.i. This was comparable with that of 18F-FBEM-Cys40-exendin-4 (9.67±2.19%ID/g at 1h p.i.). The tumor to muscle uptake ratios of 18F-FBEM-Cys39-exendin-4 were 23.81±5.83, 52.68±8.06 ,102.11±15.73 at 30, 60 and 120min p.i. respectively. The tumor uptake of 18F-FBEM-Cys39-exendin-4 can be blocked completely by excess cys39-exendin-4 added. Conclusions 18F-FBEM-Cys39-exendin-4 exhibited GLP-1R specific targeting properties in INS-1 insulinoma. It suggests that Cys replacement Ser is reasonable and credible. Research Support This work was partially supported by National Natural Science Foundation (81171399 and 81101077,2012ZX09505-001-001), Jiangsu Province Foundation (BE2012622, BK2011166,BL2012031,RC2011095), CSC Foundation (2011832173).