Preliminary evaluation of (18)F-AlF-NOTA-MAL-Cys(40)-Exendin-4 in rodent heart after myocardial ischemia and reperfusion

Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) exert cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in animal models and human clinical trials. Receptor imaging with positron emission tomography (PET) provides a non-invasive method for monitoring GLP-1R expression. In the present study, a fluorine-18-labeled aluminum fluoride exendin-4 analog [(18)F-AlF conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA)-maleimide (MAL)-Cys(40)-exendin-4] was synthesized and evaluated in a rat MI/R model for GLP-1R imaging. NOTA-MAL-Cys(40)-exendin-4 was synthesized by coupling Cys(40)-exendin-4 with NOTA-MAL. NOTA-MAL-Cys(40)-exendin-4 was then conjugated with (18)F-AlF to obtain (18)F-AlF-NOTA-MAL-Cys(40)-exendin-4. The yield of (18)F-AlF-NOTA-MAL-Cys(40)-exendin-4 was 18.5±3.4% (not decay corrected). The process was completed within ~30 min. In rat MI/R models, the tracer exhibited specific binding to GLP-1R and an appropriate signal-to-noise ratio. At 8 h post-MI/R, tracer uptake reached its peak [0.35±0.053% of injected dose (%ID)/g; n=6] in ischemic myocardium. Localized tracer uptake decreased 1 day (0.20±0.032 %ID/g; n=6) and 3 days (0.16±0.017 %ID/g; n=6) post-MI/R compared with 8 h post-MI/R, but still remained higher compared with sham-operated groups (0.06±0.012 %ID/g; n=6). Pre-injected unlabeled exendin-4 effectively blocked tracer accumulation (0.09±0.041 %ID/g; n=6). In conclusion, (18)F-AlF-NOTA-MAL-Cys(40)-exendin-4 demonstrated favorable characteristics for GLP-1R imaging following MI/R. PET imaging using (18)F-AlF-NOTA-MAL-Cys(40)-exendin-4 in rodent hearts after MI/R revealed a dynamic pattern of GLP-1R upregulation.