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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).

SUBMITTER: Mitran B

PROVIDER: S-EPMC6863848 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Mitran Bogdan B Thisgaard Helge H Rinne Sara S Dam Johan Hygum JH Azami Frishta F Tolmachev Vladimir V Orlova Anna A Rosenström Ulrika U

Scientific reports 20191119 1

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 ...[more]

PMID: 31745219

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Project description:This study was designed to analyze the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR) antagonist PET tracer, 68Ga-RM26; to assess its clinical diagnostic value in prostate cancer patients; and to perform a direct comparison between GRPR antagonist 68Ga-RM26 and agonist 68Ga-BBN. Methods: Five healthy volunteers were enrolled to validate the safety of 68Ga-RM26 and calculate dosimetry. A total of 28 patients with prostate cancer (17 newly diagnosed and 11 posttherapy) were recruited and provided written informed consent. All the cancer patients underwent PET/CT at 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-RM26. Among them, 22 patients (11 newly diagnosed and 11 posttherapy) underwent 68Ga-BBN PET/CT for comparison within 1 wk. 99mTc-MDP (methylene diphosphonate) bone scans were obtained within 2 wk for comparison. GRPR immunohistochemical staining of tumor samples was performed. Results: The administration of 68Ga-M26 was well tolerated by all subjects, with no adverse symptoms being noticed or reported during the procedure and at 2-wk follow-up. The total effective dose equivalent and effective dose were 0.0912 ± 0.0140 and 0.0657 ± 0.0124 mSv/MBq, respectively. In the 17 patients with newly diagnosed prostate cancer, 68Ga-RM26 PET/CT showed positive prostate-confined findings in 15 tumors with an SUVmax of 6.49 ± 2.37. In the 11 patients who underwent prostatectomy or brachytherapy with or without androgen deprivation therapy, 68Ga-RM26 PET/CT detected 8 metastatic lymph nodes in 3 patients with an SUVmax of 4.28 ± 1.25 and 21 bone lesions in 8 patients with an SUVmax of 3.90 ± 3.07. Compared with 68Ga-RM26 PET/CT, GRPR agonist 68Ga-BBN PET/CT detected fewer primary lesions and lymph node metastases as well as demonstrated lower tracer accumulation. There was a significant positive correlation between SUV derived from 68Ga-RM26 PET and the expression level of GRPR (P < 0.001). Conclusion: This study indicates the safety and significant efficiency of GRPR antagonist 68Ga-RM26. 68Ga-RM26 PET/CT would have remarkable value in detecting both primary prostate cancer and metastasis. 68Ga-RM26 is also expected to be better than GRPR agonist as an imaging marker to evaluate GRPR expression in prostate cancer.

Project description:Expression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer suggests that this receptor can be used as a potential molecular target to visualize and treat these tumors. We have previously investigated an antagonist analog of bombesin (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) via a diethylene glycol (PEG2) spacer (NOTA-P2-RM26) labeled with (68)Ga and (111)In. We found that this conjugate has favorable properties for in vivo imaging of GRPR-expression. The focus of this study was to develop a (18)F-labelled PET agent to visualize GRPR. NOTA-P2-RM26 was labeled with (18)F using aluminum-fluoride chelation. Stability, in vitro binding specificity and cellular processing tests were performed. The inhibition efficiency (IC50) of the [(nat)F]AlF-NOTA-P2-RM26 was compared to that of the (nat)Ga-loaded peptide using (125)I-Tyr(4)-BBN as the displacement radioligand. The pharmacokinetics and in vivo binding specificity of the compound were studied. NOTA-P2-RM26 was labeled with (18)F within 1 h (60-65% decay corrected radiochemical yield, 55 GBq/µmol). The radiopeptide was stable in murine serum and showed high specific binding to PC-3 cells. [(nat)F]AlF-NOTA-P2-RM26 showed a low nanomolar inhibition efficiency (IC50=4.4±0.8 nM). The internalization rate of the tracer was low. Less than 14% of the cell-bound radioactivity was internalized after 4 h. The biodistribution of [(18)F]AlF-NOTA-P2-RM26 demonstrated rapid blood clearance, low liver uptake and low kidney retention. The tumor uptake at 3 h p.i. was 5.5±0.7 %ID/g, and the tumor-to-blood, -muscle and -bone ratios were 87±42, 159±47, 38±16, respectively. The uptake in tumors, pancreas and other GRPR-expressing organs was significantly reduced when excess amount of non-labeled peptide was co-injected. The low uptake in bone suggests a high in vivo stability of the Al-F bond. High contrast PET image was obtained 3 h p.i. The initial biological results suggest that [(18)F]AlF-NOTA-P2-RM26 is a promising candidate for PET imaging of GRPR in vivo.

Dataset Information

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

Publications

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

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