Minigastrin radiotracers, such as [111In-DOTA]MG0 ([111In-DOTA-DGlu1]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 pentaGlu2-6 repeat in the peptide sequence has compromised their clinical applicability. On the other hand, truncated des(Glu)2-6-analogs, such as [111In-DOTA]MG11 ([111In-DOTA-DGlu10,desGlu2-6]minigastrin), despite their low renal uptake, show poor bioavailability and tumor targeting. [111In]CP04 ([111In-DOTA-DGlu1-6]minigastrin) acquired by Glu2-6/DGlu2-6 substitution showed promising tumor-to-kidney ratios in rodents. In the present study, we compare the biological profiles of [111In]CP04, [111In-DOTA]MG11, and [111In-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 [111In]CP04 and [111In-DOTA]MG0 in peripheral mouse blood increased, with an exceptional >14-fold improvement monitored for [111In-DOTA]MG11. In line with these findings, PA treatment increased the uptake of [111In]CP04 (8.5 ± 0.4%ID/g to 16.0 ± 2.3%ID/g) and [111In-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 [111In-DOTA]MG11 was >6-fold (2.5 ± 0.9%ID/g to 15.1 ± 1.7%ID/g). Interestingly, kidney uptake remained lowest for [111In-DOTA]MG11, but unfavorably increased by PA treatment for [111In-DOTA]MG0. Thus, overall, the most favorable in vivo profile was displayed by [111In-DOTA]MG11 during NEP inhibition, highlighting the need to validate this promising concept in the clinic.

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Keywords cholecystokinin subtype 2-receptor, Glu2-6-modified minigastrin, kidney retention, minigastrin radioligand, neutral endopeptidase, phosphoramidon, tumor targeting
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Journal Cancer Biotherapy and Radiopharmaceuticals
Kaloudi, A, Nock, B.A, Lymperis, E, Krenning, E.P, de Jong, M, & Maina, T. (2016). Improving the in Vivo Profile of Minigastrin Radiotracers: A Comparative Study Involving the Neutral Endopeptidase Inhibitor Phosphoramidon. Cancer Biotherapy and Radiopharmaceuticals, 31(1), 20–28. doi:10.1089/cbr.2015.1935