Radiolabelled GLP-1 analogues for in vivo targeting of insulinomas

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(939) 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(939) 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(939) 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(939) exhibited similar IC50 values (13.5, 14.4 and 13.4?n m, respectively) and bound to 26x103, 41x103 and 37?x?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(939) 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(939) 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(939) is not suited for in vivo targeting of the GLP-1R. Copyright (c) 2012 John Wiley & Sons, Ltd.