Abstract
Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. We have recently used 55Co (T1/2 = 17.5 h) as a label for next day PET imaging of GRPR expression obtaining high imaging contrast. The radionuclide-chelator combination can significantly influence the biodistribution of radiopeptides. Therefore, in this study, we hypothesized that the properties of 55Co-labeled PEG2-RM26 can be improved by identifying the optimal macrocyclic chelator. All analogues (X-PEG2-RM26, X = NOTA,NODAGA,DOTA,DOTAGA) were successfully labeled with radiocobalt with high yields and demonstrated high stability. The radiopeptides bound specifically and with picomolar affinity to GRPR and their cellular processing was characterized by low internalization. The best binding capacity was found for DOTA-PEG2-RM26. Ex vivo biodistribution in PC-3 xenografted mice was characterized by rapid blood clearance via renal excretion. Tumor uptake was similar for all conjugates at 3 h pi, exceeding the uptake in all other organs. Higher kidney uptake and longer retention were associated with N-terminal negative charge (DOTAGA-containing conjugate). Tumor-to-organ ratios increased over time for all constructs, although significant chelator-dependent differences were observed. Concordant with affinity measurements, DOTA-analog had the best retention of activity in tumors, resulting in the highest tumor-to-blood ratio 24 h pi, which translated into high contrast PET/CT imaging (using 55Co).
Highlights
Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer
We have previously reported on an antagonistic analogue of bombesin NOTA-PEG2-RM26 labeled with 111In and 68Ga that had a favorable biodistribution profile with a high and specific GRPR-mediated tumor uptake[11]
Receptors for small regulatory peptides are often overexpressed in human tumors. One example of such receptors are GRPRs, which are overexpressed in early prostate cancer and can be targeted for diagnostic imaging and therapy of oligometastatic prostate cancer. Peptides such as the bombesin-based ligands targeting GRPRs are attractive for radionuclide molecular imaging due to their relatively small size which translates into fast blood clearance, fast tumor penetration and inexpensive production
Summary
Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. Oligometastatic disease is defined as an intermediate state in prostate cancer progression characterized by limited metastatic spread[1]. Biopsies are invasive, have a high sampling error of up to 40%, and can lead to severe complications[4] These diagnostic modalities cannot www.nature.com/scientificreports differentiate between local, regional, and distant disease, which is a prerequisite for oligometastatic prostate cancer diagnosis. These major limitations of the main prostate cancer diagnostic tools place molecular imaging in a unique position where it can significantly contribute in the initial diagnosis and patient stratification, and in monitoring the response to therapy. Despite its significant potential, molecular imaging of oligometastatic prostate cancer is not without challenges, and the highest sensitivity and specificity are required for imaging of small metastases[5]
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