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

Introduction: 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-DGlu10]gastrin(10-17) analogs, with oxidation-susceptible Met15 replaced by: Ahp15 (1), Nle15 (2), or Leu15 (3), and study the profile of [111In]1/2/3 during in vivo inhibition of neutral endopeptidase (NEP) in comparison to the non-truncated [111In-DOTA,DGlu5]gastrin(5-17) ([111In]4) reference. Methods: Blood samples collected from mice 5min postinjection (pi) of [111In]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 [111In]1/2/3/4 without or with PA coinjection. Results: Firstly, we observed remarkable increases in the amount of radiopeptides detected intact in the blood of PA-treated mice at 5min pi compared to controls. Secondly, we noted impressive enhancement of [111In]1/2/3 localization in AR42J and A431-CCK2R(+) tumors in mice after PA coinjection. Specifically, the uptake of [111In]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 [111In]2 and [111In]3 as well. Thirdly, renal uptake remained favorably low and unaffected by PA (<2.5%ID/g). Conversely, although the stability and tumor targeting of [111In]4 improved, its high renal uptake (>85%ID/g) increased even further by PA (>140%ID/g). Conclusions: 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.

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