title: In vivo inhibition of neutral endopeptidase enhances the diagnostic potential of truncated gastrin (111)In-radioligands.
abstract: BACKGROUND
  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.
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10, Athens, Greece.
authors: Aikaterini
authors: A
authors: Kaloudi
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10, Athens, Greece.
authors: Berthold A
authors: BA
authors: Nock
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10, Athens, Greece.
authors: Emmanouil
authors: E
authors: Lymperis
authors: piCHEM, A-8045, Graz, Austria.
authors: Werner
authors: W
authors: Sallegger
authors: Department of Nuclear Medicine, Erasmus MC, 3015 CE, Rotterdam, The Netherlands.
authors: Eric P
authors: EP
authors: Krenning
authors: Department of Nuclear Medicine, Erasmus MC, 3015 CE, Rotterdam, The Netherlands; Department of Radiology, Erasmus MC, 3015 CE, Rotterdam, The Netherlands.
authors: Marion
authors: M
authors: de Jong
authors: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10, Athens, Greece. Electronic address: maina_thea@hotmail.com.
authors: Theodosia
authors: T
authors: Maina
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005755:Gastrins / Q000737:chemistry* / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007205:Indium Radioisotopes; D008024:Ligands; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000737:chemistry*; D011854:Radiochemistry; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D005755:Gastrins; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008024:Ligands; D011480:Protease Inhibitors; D043887:Receptor, Cholecystokinin B; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D015260:Neprilysin
keywords: Cholecystokinin subtype 2-receptor; Neutral endopeptidase inhibition; Phosphoramidon; Radiolabeled gastrin; Truncated gastrin; Tumor imaging