(99m)Tc-labeled gastrins of varying peptide chain length: Distinct impact of NEP/ACE-inhibition on stability and tumor uptake in mice.
In situ inhibition of neutral endopeptidase (NEP) has been recently shown to impressively increase the bioavailability and tumor uptake of biodegradable gastrin radioligands. Furthermore, angiotensin converting enzyme (ACE) has been previously shown to cleave gastrin analogs in vitro. In the present study, we have assessed the effects induced by single or dual NEP/ACE-inhibition on the pharmacokinetic profile of three (99m)Tc-labeled gastrins of varying peptide chain length: [(99m)Tc]SG6 ([(99m)Tc-N4-Gln(1)]gastrin(1-17)), [(99m)Tc]DG2 ([(99m)Tc-N4-Gly(4),DGlu(5)]gastrin(4-17)) and [(99m)Tc]DG4 ([(99m)Tc-N4-DGlu(10)]gastrin(10-17)).



Mouse blood samples were collected 5min after injection of each of [(99m)Tc]SG6/DG2/DG4 together with: a) vehicle, b) the NEP-inhibitor phosphoramidon (PA), c) the ACE-inhibitor lisinopril (Lis), or d) PA plus Lis and were analyzed by RP-HPLC for radiometabolite detection. Biodistribution was studied in SCID mice bearing A431-CCK2R(+/-) xenografts at 4h postinjection (pi). [(99m)Tc]SG6 or [(99m)Tc]DG4 was coinjected with either vehicle or the above described NEP/ACE-inhibitor regimens; for [(99m)Tc]DG2 control and PA animal groups were only included.



Treatment of mice with PA induced significant stabilization of (99m)Tc-radiotracers in peripheral blood, while treatment with Lis or Lis+PA affected the stability of des(Glu)5 [(99m)Tc]DG4 only. In line with these findings, PA coinjection led to notable amplification of tumor uptake of radiopeptides compared to controls (P<0.01). Only [(99m)Tc]DG4 profited by single Lis (2.06±0.39%ID/g vs 0.99±0.13%ID/g in controls) or combined Lis+PA coinjection (8.91±1.61%ID/g vs 4.89±1.33%ID/g in PA-group). Furthermore, kidney uptake remained favourably low and unaffected by PA and/or Lis coinjection only in the case of [(99m)Tc]DG4 (<1.9%ID/g) resulting in the most optimal tumor-to-kidney ratios.



In situ NEP/ACE-inhibition diversely affected the in vivo profile of (99m)Tc-radioligands based on different-length gastrins. Truncated [(99m)Tc]DG4 exhibited overall the most attractive profile during combined NEP/ACE-inhibition in mouse models, providing new opportunities for CCK2R-expressing tumor imaging in man with SPECT.
Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10 Athens, Greece.
Aikaterini
A
Kaloudi
Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10 Athens, Greece.
Berthold A
BA
Nock
Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10 Athens, Greece.
Emmanouil
E
Lymperis
Department of Nuclear Medicine, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
Eric P
EP
Krenning
Department of Nuclear Medicine, Erasmus MC, 3015 CE Rotterdam, The Netherlands; Department of Radiology, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
Marion
M
de Jong
Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos", GR-153 10 Athens, Greece. Electronic address: maina_thea@hotmail.com.
Theodosia
T
Maina
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005755:Gastrins / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007553:Isotope Labeling; D007700:Kinetics; D051379:Mice; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D043887:Receptor, Cholecystokinin B / Q000378:metabolism; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005755:Gastrins; D043887:Receptor, Cholecystokinin B; D013667:Technetium; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin
ACE-inhibition; Gastrin-based (99m)Tc-radiotracers; Kidney retention; NEP-inhibition; Radioligand stabilization; Tumor targeting