Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe (18)F-FBEM-Cys (39)-exendin-4.
OBJECTIVE
Glucagon-like peptide-1 receptor (GLP-1R) is a specific target for insulinomas imaging since it is overexpressed in the tumor. Exendin-4 exhibits high affinity for the GLP-1R. In this study, a novel (18)F-labeled exendin-4 analog, (18)F-FBEM-Cys(39)-exendin-4, was synthesized and its potentials for GLP-1R imaging were also evaluated.


METHODS
(18)F-FBEM was synthesized by coupling (18)F-fluorobenzoic acid ((18)F-FBA) with N-(2-aminoethyl) maleimide, and the reaction conditions were optimized. Cys(39)-exendin-4 was then conjugated with (18)F-FBEM to obtain (18)F-FBEM-Cys(39)-exendin-4. The GLP-1R targeting potential and pharmacokinetic profile of the tracer were analyzed in INS-1 insulinoma and MDA-MB-435 breast tumor model, respectively.


RESULTS
Under the optimal conditions, the yield of radiolabeled (18)F-FBEM was 49.1 ± 2.0 % (based on (18)F-FBA, non-decay corrected). The yield of (18)F-FBEM-Cys(39)-exendin-4 was 35.1 ± 2.6 % (based on the starting (18)F-FBEM, non-decay corrected). The radiochemical purity of (18)F-FBEM-Cys(39)-exendin-4 is >95 %, and the specific activity was at least 35 GBq/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. Low levels of radioactivity were also detected at pancreas and lungs due to few GLP-1R expressions. GLP-1R binding specificity was demonstrated by reduced INS-1 tumor uptake of the tracer after coinjection with an excess of unlabeled Cys(39)-exendin-4 at 1 h postinjection.


CONCLUSIONS
The thiol-reactive reagent, (18)F-FBEM, was prepared with high yield and successfully conjugated to Cys(39)-exendin-4. Favorable preclinical data showing specific and effective tumor targeting by (18)F-FBEM-Cys(39)-exendin-4 suggest that the tracer may be a potential probe for insulinomas imaging.
Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China, xuyuping@jsinm.org.
Yuping
Y
Xu
Donghui
D
Pan
Qing
Q
Xu
Chen
C
Zhu
Lizhen
L
Wang
Fei
F
Chen
Runlin
R
Yang
Shineng
S
Luo
Min
M
Yang
D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods*; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D007340:Insulinoma / Q000175:diagnosis* / Q000378:metabolism; D008301:Maleimides; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D010455:Peptides; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon / Q000378:metabolism*; D014688:Venoms
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D008301:Maleimides; C512447:N-(2-(4-18F-fluorobenzamido)ethyl)maleimide; D010455:Peptides; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide