Selection of an optimal macrocyclic chelator improves the imaging of prostate cancer using cobalt-labeled GRPR antagonist RM26

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).

Benefit of Later-Time-Point PET Imaging of HER3 Expression Using Optimized Radiocobalt-Labeled Affibody Molecules

“…Among other radiometals, 55 Co has the lowest positron energy, which is favorable for imaging resolution, and the branching ratio of the positron decay is the highest among the positron emitting nuclides. Previous studies have demonstrated that radiocobalt forms stable complexes with macrocyclic chelators, such as DOTA, NOTA, DOTAGA and NODAGA [37,39]. This makes it a promising candidate for later-time-point PET imaging.…”

“…We, therefore, studied the in vitro and in vivo properties of four different variants of (HE) 3 -Z HER3 (further denoted as (HE) 3 -Z HER3 -X, with X = NOTA, NODAGA, DOTA, DOTAGA) labeled with cobalt-57 and compared the most promising radiocobalt variant with 68 Ga-(HE) 3 -Z HER3 -NODAGA. Cobalt-57 is a convenient surrogate for cobalt-55 [35,37] due to its commercial availability and long half-life (272 d). A potential drawback could be different metal impurities for 55 Co and 57 Co, which may require re-optimization of the labeling procedure.…”

66Ga-PET-imaging of GRPR-expression in prostate cancer: production and characterization of [66Ga]Ga-NOTA-PEG2-RM26

“…Beyond the 4 h the internalized fraction of [ 66 Ga]Ga-NOTA-PEG 2 -RM26 remained low, with only 17% of the total cell associated activity internalized after 24 h. Slow internalization was expected due to the antagonistic properties of RM26. However, the low level of internalized activity resembled the behavior of radiocobalt-labeled NOTA-PEG 2 -RM26 22,39 , and was considerably lower than the level of internalization of its [ 111 In]In-labeled analog 21 . Similar to [ 55/57 Co]Co-PEG 2 -RM26, the radiocobalt label also led to lower amounts of internalized activity with affibody molecules, and it is hypothesized that the radiocobalt label leaks from or is transported out of the cell by specific cobalt-efflux mechanisms 22,[39][40][41] .…”

New Frontiers in Molecular Imaging Using Peptide-Based Radiopharmaceuticals for Prostate Cancer

“…Changing PEG chain length had little effect on improving the tumor-to-background ratio, and PEG 2 , PEG 3 , and PEG 4 linkers displayed similarly high tumor uptake and low kidney radioactivity uptake (Varasteh et al, 2014(Varasteh et al, , 2015Gourni et al, 2015). Additionally, this RM26 peptide showed superior characteristics for SPECT imaging when labeled with 111 In, cobalt-55 ( 55 Co), and cobalt-57 ( 57 Co) (Mitran et al, 2016(Mitran et al, , 2017(Mitran et al, , 2019. Copper-64 ( 64 Cu, beta + , Emax = 0.656 MeV; gamma, 10%; T1/2 = 16.7 h) is also an ideal positron-emitting radionuclide for PET diagnosis.…”