• GLP-1;
  • exendin;
  • antagonist;
  • agonist;
  • insulinoma

Internalizing agonists are usually selected for peptide receptor targeting. There is increasing evidence that non-internalizing receptor antagonists can be used for this purpose. We investigated whether the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin(9–39) can be used for in vivo targeting of GLP-1R expressing tumours and compared the in vitro and in vivo characteristics with the GLP-1R agonists exendin-3 and exendin-4. The binding and internalization kinetics of labelled [Lys40(DTPA)]exendin-3, [Lys40(DTPA)]exendin-4 and [Lys40(DTPA)]exendin(9–39) were determined in vitro using INS-1 cells. The in vivo targeting properties of [Lys40(111In-DTPA)]exendin-3, [Lys40(111In-DTPA)]exendin-4 and [Lys40(111In-DTPA)]exendin(9–39) were examined in BALB/c nude mice with subcutaneous INS-1 tumours. natIn-labelled [Lys40(DTPA)]exendin-3, [Lys40(DTPA)]exendin-4 and [Lys40(DTPA)]exendin(9–39) exhibited similar IC50 values (13.5, 14.4 and 13.4 n m, respectively) and bound to 26 × 103, 41 × 103 and 37 × 103 receptors per cell, respectively. [Lys40(111In-DTPA)]exendin-3 and [Lys40(111In-DTPA)]exendin-4 showed rapid in vitro binding and internalization kinetics, whereas [Lys40(111In-DTPA)]exendin(9–39) showed lower binding and minimal internalization in vitro. In mice, high specific uptake of [Lys40(111In-DTPA)]exendin-3 [25.0 ± 6.0% injected dose (ID) g−1] in the tumour was observed at 0.5 h post-injection (p.i.) with similar uptake up to 4 h p.i. [Lys40(111In-DTPA)]exendin-4 showed higher tumour uptake at 1 and 4 h p.i. (40.8 ± 7.0 and 41.9 ± 7.2% ID g−1, respectively). Remarkably, [Lys40(111In-DTPA)]exendin(9–39) showed only low specific uptake in the tumour at 0.5 h p.i. (3.2 ± 0.7% ID g−1), rapidly decreasing over time. In conclusion, the GLP-1R agonists [Lys40(DTPA)]exendin-3 and [Lys40(DTPA)]exendin-4 labelled with 111In could be useful for in vivo GLP-1R targeting, whereas [Lys40(DTPA)]exendin(9–39) is not suited for in vivo targeting of the GLP-1R. Copyright © 2012 John Wiley & Sons, Ltd.