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

A Kaloudi, Berthold Nock, E Lymperis, W Sallegger, Eric Krenning, Marion Jong, T Maina

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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 [DOTADGIu(10)]gastrin(10-17) analogs, with oxidation-susceptible Met(15) replaced by: Ahp(15) (1), Nle(15) (2), or Leu(15) (3), and study the profile of [In-111]1/2/3 during in vivo inhibition of neutral endopeptidase (NEP) in comparison to the non-truncated [In-111-DOTA,DGIu(5)]gastrin(5-17) ([111In]4) reference. Methods: Blood samples collected from mice 5 min postinjection (pi) of [In-111]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 4 h after administration of [In-111]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 5 min pi compared to controls. Secondly, we noted impressive enhancement of [In-111]1/2/3 localization in AR42J and A431-CCIQR(+) tumors in mice after PA coinjection. Specifically, the uptake of [In-111]1 at 4 h pi increased from 2.6 +/- 03%ID/g to 13.3 +/- 3.5%ID/g in the AR42J tumors and from 43 +/- 0.6%ID/g to 20.4 +/- 3.6%ID/g in the A431-CCK2R(+) xenografts, with comparable improvements noted for [In-111]2 and [In-111] as well. Thirdly, renal uptake remained favorably low and unaffected by PA (<2.5%ID/g). Conversely, although the stability and tumor targeting of [In-111]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. (C) 2015 Elsevier Inc. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)824-832
Number of pages9
JournalNuclear Medicine and Biology
Issue number11
Publication statusPublished - 2015

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