Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin (177)Lu-PP-F11N

SIMPLE SUMMARY: Several radiolabeled peptides targeting CCK2R-positive types of cancer (such as medullary thyroid cancer and small cell lung cancer) have been reported in the last 25 years, some of which have entered clinical trials. In an effort to improve its tumor-targeting properties, we applied chemical modifications to the backbone of the peptide (177)Lu-PP-F11N, an analog of minigastrin in clinical trials. The generated radiolabeled peptidomimetics showed significantly improved characteristics in mice bearing CCK2R-positive tumor xenografts, such as higher tumor uptake, slower tumor washout, and increased tumor-to-kidney ratios. These properties make the novel compounds promising candidates for the imaging and therapy of CCK2R-positive tumors and metastases. ABSTRACT: The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with (177)Lu(3+), and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT/CT imaging). NMGs with triazoles inserted between the amino acids DGlu(10)-Ala(11) and/or Tyr(12)-Gly(13) showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms.