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

Abstract：

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-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. METHODS: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. 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 [(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 (<2.5%ID/g). Conversely, although the stability and tumor targeting of [(111)In]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.

journal_name

Nucl Med Biol

journal_title

Nuclear medicine and biology

authors

Kaloudi A,Nock BA,Lymperis E,Sallegger W,Krenning EP,de Jong M,Maina T

doi

10.1016/j.nucmedbio.2015.07.009

subject

Has Abstract

pub_date

2015-11-01 00:00:00

pages

824-32

issue

eissn

0969-8051

issn

1872-9614

pii

S0969-8051(15)00131-6

journal_volume

pub_type

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