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(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 [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) were determined in vitro using INS-1 cells. The in vivo targeting properties of [Lys(40) ((111) In-DTPA)]exendin-3, [Lys(40) ((111) In-DTPA)]exendin-4 and [Lys(40) ((111) In-DTPA)]exendin(9-39) were examined in BALB/c nude mice with subcutaneous INS-1 tumours. (nat) In-labelled [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) exhibited similar IC(50) values (13.5, 14.4 and 13.4 n m, respectively) and bound to 26 × 10(3) , 41 × 10(3) and 37 × 10(3) receptors per cell, respectively. [Lys(40) ((111) In-DTPA)]exendin-3 and [Lys(40) ((111) In-DTPA)]exendin-4 showed rapid in vitro binding and internalization kinetics, whereas [Lys(40) ((111) In-DTPA)]exendin(9-39) showed lower binding and minimal internalization in vitro. In mice, high specific uptake of [Lys(40) ((111) In-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. [Lys(40) ((111) In-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, [Lys(40) ((111) In-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 [Lys(40) (DTPA)]exendin-3 and [Lys(40) (DTPA)]exendin-4 labelled with (111) In could be useful for in vivo GLP-1R targeting, whereas [Lys(40) (DTPA)]exendin(9-39) is not suited for in vivo targeting of the GLP-1R.