title: Improving the In Vivo Profile of Minigastrin Radiotracers: A Comparative Study Involving the Neutral Endopeptidase Inhibitor Phosphoramidon.
abstract: Minigastrin radiotracers, such as [(111)In-DOTA]MG0 ([(111)In-DOTA-DGlu(1)]minigastrin), have been considered for diagnostic imaging and radionuclide therapy of CCK2R-positive human tumors, such as medullary thyroid carcinoma. However, the high kidney retention assigned to the pentaGlu(2-6) repeat in the peptide sequence has compromised their clinical applicability. On the other hand, truncated des(Glu)(2-6)-analogs, such as [(111)In-DOTA]MG11 ([(111)In-DOTA-DGlu(10),desGlu(2-6)]minigastrin), despite their low renal uptake, show poor bioavailability and tumor targeting. [(111)In]CP04 ([(111)In-DOTA-DGlu(1-6)]minigastrin) acquired by Glu(2-6)/DGlu(2-6) substitution showed promising tumor-to-kidney ratios in rodents. In the present study, we compare the biological profiles of [(111)In]CP04, [(111)In-DOTA]MG11, and [(111)In-DOTA]MG0 during in situ neutral endopeptidase (NEP) inhibition, recently shown to improve the bioavailability of several peptide radiotracers. After coinjection of the NEP inhibitor, phosphoramidon (PA), the stability of [(111)In]CP04 and [(111)In-DOTA]MG0 in peripheral mouse blood increased, with an exceptional >14-fold improvement monitored for [(111)In-DOTA]MG11. In line with these findings, PA treatment increased the uptake of [(111)In]CP04 (8.5 ± 0.4%ID/g to 16.0 ± 2.3%ID/g) and [(111)In-DOTA]MG0 (11.9 ± 2.2%ID/g to 17.2 ± 0.9%ID/g) in A431-CCK2R(+) tumors at 4 hours postinjection, whereas the respective increase for [(111)In-DOTA]MG11 was >6-fold (2.5 ± 0.9%ID/g to 15.1 ± 1.7%ID/g). Interestingly, kidney uptake remained lowest for [(111)In-DOTA]MG11, but unfavorably increased by PA treatment for [(111)In-DOTA]MG0. Thus, overall, the most favorable in vivo profile was displayed by [(111)In-DOTA]MG11 during NEP inhibition, highlighting the need to validate this promising concept in the clinic.
authors: 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece .
authors: Aikaterini
authors: A
authors: Kaloudi
authors: 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece .
authors: Berthold A
authors: BA
authors: Nock
authors: 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece .
authors: Emmanouil
authors: E
authors: Lymperis
authors: 2 Department of Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands .
authors: Eric P
authors: EP
authors: Krenning
authors: 2 Department of Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands .|3 Department of Radiology, Erasmus MC , Rotterdam, The Netherlands .
authors: Marion
authors: M
authors: de Jong
authors: 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece .
authors: Theodosia
authors: T
authors: Maina
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000378:metabolism; D005755:Gastrins / Q000493:pharmacokinetics*; D006020:Glycopeptides / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D005755:Gastrins; D006020:Glycopeptides; D011480:Protease Inhibitors; D019275:Radiopharmaceuticals; C008530:minigastrin; D015260:Neprilysin; C008890:phosphoramidon
keywords: Glu2–6-modified minigastrin; cholecystokinin subtype 2-receptor; kidney retention; minigastrin radioligand; neutral endopeptidase; phosphoramidon; tumor targeting