Metabolically-stabilized 68Ga-NOTA-bombesin for PET Imaging of prostate cancer and influence of protease inhibitor Phosphoramidon.

Peptide receptor-based targeted molecular imaging and therapy of cancer is on the current forefront of nuclear medicine preclinical research and clinical practice. The frequent overexpression of gastrin-releasing peptide (GRP) receptor in prostate cancer prompted the development of radiolabeled bombesin derivatives as high affinity peptidic ligands for selective targeting of the GRP receptor.

In this study, we have evaluated a novel 68Ga-labeled bombesin derivative for its ability to image prostate cancer in vivo. In addition, we were interested in the application of the recently proposed "serve-and-protect" strategy regarding metabolic stability of radiolabeled peptides in vivo and their enhanced tumor uptake. GRP receptor targeting peptides NOTA-BBN2 and natGa-NOTA-BBN2 demonstrated characteristic antagonistic properties and high binding affinity towards the GRP receptor in PC3 cells (IC50 4.6-8.2 nM). Radiolabeled peptide 68Ga-NOTA-BBN2 was obtained from NOTA-BBN2 in RCY greater 62% d.c. within 35 min including purification. 68Ga-NOTA-BBN2 exhibits great resistance against degradation by peptidases in vivo within the investigated time frame of 60 min. Interestingly, stability was not further enhanced in the presence of protease inhibitor phosphoramidon. Dynamic PET studies showed high tumor uptake in both, PC3- and LNCaP-bearing BALB/c nude mice (SUV5min >0.6 and SUV60min >0.5). PET radiotracer 68Ga-NOTA-BBN2 represents a novel radiometal-labeled bombesin derivative for suitable targeting of GRP receptor in PC3 and LNCaP prostate cancer-bearing mice. A further increase of its high metabolic stability profile in vivo and favourable tumor uptake by co-administration of protease inhibitor phosphoramidon was not successful and lead to the conclusion that the "serve-and-protect" strategy may not be valid for already stabilized peptide structures in vivo.

Molecular pharmaceutics. 2016 Mar 14 [Epub ahead of print]

Susan Richter, Melinda Wuest, Cody N Bergman, Stephanie Krieger, Buck E Rogers, Frank Wuest