In vivo inhibition of neutral endopeptidase enhances the diagnostic potential of truncated gastrin (111)In-radioligands

• Published in: Nuclear medicine and biology 2015-11, Vol.42 (11), p.824-832
• Main Authors: Kaloudi, Aikaterini, Nock, Berthold A, Lymperis, Emmanouil, Sallegger, Werner, Krenning, Eric P, de Jong, Marion, Maina, Theodosia
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Line, Tumor; Gastrins - chemistry; Gastrins - pharmacokinetics; Heterocyclic Compounds, 1-Ring - chemistry; Humans; Indium Radioisotopes; Ligands; Male; Mice; Molecular Sequence Data; Neprilysin - antagonists & inhibitors; Protease Inhibitors - chemistry; Radiochemistry; Rats; Receptor, Cholecystokinin B - metabolism; Tissue Distribution
• ISSN: 1872-9614
• DOI: 10.1016/j.nucmedbio.2015.07.009

Radiolabeled gastrin analogs represent attractive candidates for diagnosis and therapy of cholecystokinin subtype-2 receptor (CCK2R)-expressing tumors. Radiolabeled des(Glu)5-gastrins show favorably low renal accumulation, but localize poorly in CCK2R-positive lesions. We introduce herein three truncated [DOTA-DGlu(10)]gastrin(10-17) analogs, with oxidation-susceptible Met(15) replaced by: (1), (2), or (3), and study the profile of [(111)In]1/2/3 during in vivo inhibition of neutral endopeptidase (NEP) in comparison to the non-truncated [ ([(111)In]4) reference. Blood samples collected from mice 5 min postinjection (pi) of [(111)In]1/2/3/4 without or with phosphoramidon (PA) coinjection were analyzed by RP-HPLC. Biodistribution was conducted in SCID mice bearing A431-CCK2R(+) or AR42J xenografts 4h after administration of [(111)In]1/2/3/4 without or with PA coinjection. Firstly, we observed remarkable increases in the amount of radiopeptides detected intact in the blood of PA-treated mice at 5 min pi compared to controls. Secondly, we noted impressive enhancement of [(111)In]1/2/3 localization in AR42J and A431-CCK2R(+) tumors in mice after PA coinjection. Specifically, the uptake of [(111)In]1 at 4h pi increased from 2.6 ± 0.3%ID/g to 13.3 ± 3.5%ID/g in the AR42J tumors and from 4.3 ± 0.6%ID/g to 20.4 ± 3.6%ID/g in the A431-CCK2R(+) xenografts, with comparable improvements noted for [(111)In]2 and [(111)In]3 as well. Thirdly, renal uptake remained favorably low and unaffected by PA (85%ID/g) increased even further by PA (>140%ID/g). In situ inhibition of NEP represents a promising new tool to enhance the diagnostic efficacy of biodegradable gastrin radioligands in the visualization of CCK2R-positive lesions in man.