Improving the In Vivo Profile of Minigastrin Radiotracers: A Comparative Study Involving the Neutral Endopeptidase Inhibitor Phosphoramidon

Abstract

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 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 [¹¹¹In-DOTA]MG11 ([¹¹¹In-DOTA-DGlu¹⁰,desGlu^2–6]minigastrin), despite their low renal uptake, show poor bioavailability and tumor targeting. [¹¹¹In]CP04 ([¹¹¹In-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 [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.