Open AccessRadiolabelled GLP‐1 analogues for in vivo targeting of insulinomas
Author(s) -
Brom Maarten,
Joosten Lieke,
Oyen Wim J. G.,
Gotthardt Martin,
Boerman Otto C.
Publication year - 2012
Publication title -
contrast media & molecular imaging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.714
H-Index - 50
eISSN - 1555-4317
pISSN - 1555-4309
DOI - 10.1002/cmmi.475
Subject(s) - internalization , in vivo , in vitro , receptor , antagonist , chemistry , peptide , glucagon like peptide 1 , pharmacology , medicine , endocrinology , biochemistry , microbiology and biotechnology , biology , type 2 diabetes , diabetes mellitus
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. Copyright © 2012 John Wiley & Sons, Ltd.