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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

ABSTRACT: Radiolabeled bombesin (BBN) analogs that bind to the gastrin-releasing peptide receptor (GRPR) represent a topic of active investigation for the development of molecular probes for PET or SPECT of prostate cancer (PCa). RM1 and AMBA have been identified as the 2 most promising BBN peptides for GRPR-targeted cancer imaging and therapy. In this study, to develop a clinically translatable BBN-based PET probe, we synthesized and evaluated (18)F-AlF- (aluminum-fluoride) and (64)Cu-radiolabeled RM1 and AMBA analogs for their potential application in PET imaging of PCa.1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA)-conjugated RM1 and AMBA were synthesized and tested for their GRPR-binding affinities. The NODAGA-RM1 and NODAGA-AMBA probes were further radiolabeled with (64)Cu or (18)F-AlF and then evaluated in a subcutaneous PCa xenograft model (PC3) by small-animal PET imaging and biodistribution studies.NODAGA-RM1 and NODAGA-AMBA can be successfully synthesized and radiolabeled with (64)Cu and (18)F-AlF. (64)Cu- and (18)F-AlF-labeled NODAGA-RM1 demonstrated excellent serum stability and tumor-imaging properties in the in vitro stability assays and in vivo imaging studies. (64)Cu-NODAGA-RM1 exhibited tumor uptake values of 3.3 ± 0.38, 3.0 ± 0.76, and 3.5 ± 1.0 percentage injected dose per gram of tissue (%ID/g) at 0.5, 1.5, and 4 h after injection, respectively. (18)F-AlF-NODAGA-RM1 exhibited tumor uptake values of 4.6 ± 1.5, 4.0 ± 0.87, and 3.9 ± 0.48 %ID/g at 0.5, 1, and 2 h, respectively.The high-stability, efficient tumor uptake and optimal pharmacokinetic properties highlight (18)F-AlF-NODAGA-RM1 as a probe with great potential and clinical application for the PET imaging of prostate cancer.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4215198 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

Liu Yang Y Hu Xiang X Liu Hongguang H Bu Lihong L Ma Xiaowei X Cheng Kai K Li Jinbo J Tian Mei M Zhang Hong H Cheng Zhen Z

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20131106 12

<h4>Unlabelled</h4>Radiolabeled bombesin (BBN) analogs that bind to the gastrin-releasing peptide receptor (GRPR) represent a topic of active investigation for the development of molecular probes for PET or SPECT of prostate cancer (PCa). RM1 and AMBA have been identified as the 2 most promising BBN peptides for GRPR-targeted cancer imaging and therapy. In this study, to develop a clinically translatable BBN-based PET probe, we synthesized and evaluated (18)F-AlF- (aluminum-fluoride) and (64)Cu- ...[more]

PMID: 24198391

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Project description:BACKGROUND:Among the many peptide receptor systems, gastrin-releasing-peptide (GRP) receptors, the mammalian equivalent of bombesin (BN) receptors, are potential targets for diagnosis and therapy of breast tumors due to their overexpression in various frequently occurring human cancers. The aim of this study was to synthesize and comparative evaluation of 99mTc-labeled new BN peptide analogs. Four new BN analogs, HYNIC-Asp[PheNle]BN(7-14)NH2, BN1; HYNIC-Pro-Asp[TyrMet]BN(7-14)NH2, BN2; HYNIC-Asp-Asn[Lys-CHAla-Nle]BN(7-14)NH2, BN3; and DOMA-GABA[Pro-Tyr-Nle]BN(7-14)NH2, BN4 were synthesized and biologically evaluated for targeted imaging of GRP receptor-positive breast-tumors. METHODS:Solid-phase synthesis using Fmoc-chemistry was adopted for the synthesis of peptides. BN1-BN4 analogs were better over the standard Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BNS). Lipophilicity, serum stability, internalization, and binding affinity studies were carried out using 99mTc-labeled analogs. Biodistribution and imaging analyses were performed on MDA-MB-231 cell-induced tumor-bearing mice. BN-analogs induced angiogenesis; tumor formation and GRP-receptor-expression were confirmed by histology and immunohistochemistry analyses of tumor sections and important tissue sections. RESULTS:All the analogs displayed ≥ 97% purity after the HPLC purification. BN-peptide-conjugates exhibited high serum stability and significant binding affinity to GRP-positive tumor; rapid internalization/externalization in/from MDA-MB-231 cells were noticed for the BN analogs. BN4 and BN3 exhibited higher binding affinity, stability than BN1 and BN2. Highly specific in vivo uptakes to the tumor were clearly visualized by scintigraphy; rapid excretion from non-target tissues via kidneys suggests a higher tumor-to-background ratio. BN4, among all the analogs, stimulates the expression of angiogenic markers to a maximum. CONCLUSION:Considering its most improved pharmacological characteristics, BN4 is thus considered as most promising probes for early non-invasive diagnosis of GRP receptor-positive breast tumors.

Project description:PurposeThis study aimed to introduce a novel [18F]AlF-labeled ODAP-Urea-based Prostate-specific membrane antigen (PSMA) probe, named [18F]AlF-PSMA-137, which was derived from the successful modification of glutamate-like functional group. The preclinically physical and biological characteristics of the probe were analyzed. Polit clinical PET/CT translation was performed to analyze its feasibility in clinical diagnosis of prostate cancer.Methods[18F]AlF-PSMA-137 was maturely labeled with the [18F]AlF2+ labeling technique. It was analyzed by radio-HPLC for radiochemical purity and stability analysis in vitro and in vivo. The PSMA specificity was investigated in PSMA-positive (LNCaP) and PSMA-negative (PC3) cells, and the binding affinity was evaluated in LNCaP cells. Micro-PET/CT imaging was performed in mice bearing LNCaP or PC3 tumors. Thirteen patients with newly diagnosed prostate cancer were included for [18F]AlF-PSMA-137 PET/CT imaging. Physiologic biodistribution and tumor burden were semi-quantitatively evaluated and the radiation dosimetry of [18F]AlF-PSMA-137 was estimated.ResultsThe radiochemical yield of [18F]AlF-PSMA-137 was 54.2 ± 10.7% (n = 16) with the radiochemical purity over 99% and the specific activity of 26.36 ± 7.33 GBq/μmol. The binding affinity to PSMA was 2.11 ± 0.63 nM. [18F]AlF-PSMA-137 showed high cell/tumor uptake which can be specifically blocked by PSMA inhibitor. According to the biodistribution in patients, [18F]AlF-PSMA-137 was mainly accumulated in kidneys, lacrimal glands, parotid glands, submandibular glands and liver which was similar to the extensive Glu-Ureas based probes. A total of 81 lesions were detected in PET/CT imaging and over 91% of lesions increased between 1 h p.i. (SUVmean: 10.98 ± 18.12) and 2 h p.i. (SUVmean: 14.25 ± 21.28) (p < 0.001). Additionally, the probe showed intensive accumulation in lesions which provided excellent imaging contrast with the high tumor-to-muscle ratio of 15.57 ± 27.21 at 1 h p.i. and 25.42 ± 36.60 at 2 h p.i. (p < 0.001), respectively. The effective dose of [18F]AlF-PSMA-137 was estimated as 0.0119 ± 0.0009 mSv/MBq.ConclusionAn ODAP-Urea-based PSMA probe [18F]AlF-PSMA-137 was successfully prepared with high specificity and binding affinity to PSMA. Micro-PET/CT imaging study demonstrated its feasibility for prostate cancer imaging. Pilot clinical study showed its potential for delay-imaging and prostate cancer detection.

Project description:PurposeRANKL expression in the tumor microenvironment has been identified as a biomarker of immune suppression, negating the effect of some cancer immunotherapies. Previously we had developed a radiotracer based on the FDA-approved RANKL-specific antibody denosumab, [89Zr]Zr-DFO-denosumab, enabling successful immuno-PET imaging. Radiolabeled denosumab, however, showed long blood circulation and delayed tumor uptake, potentially limiting its applications. Here we aimed to develop a smaller radiolabeled denosumab fragment, [64Cu]Cu-NOTA-denos-Fab, that would ideally show faster tumor accumulation and better diffusion into the tumor for the visualization of RANKL.Experimental designFab fragments were prepared from denosumab using papain and conjugated to a NOTA chelator for radiolabeling with 64Cu. The bioconjugates were characterized in vitro using SDS-PAGE analysis, and the binding affinity was assessed using a radiotracer cell binding assay. Small animal PET imaging evaluated tumor targeting and biodistribution in transduced RANKL-ME-180 xenografts.ResultsThe radiolabeling yield of [64Cu]Cu-NOTA-denos-Fab was 58 ± 9.2%, with a specific activity of 0.79 ± 0.11 MBq/µg (n = 3). A radiotracer binding assay proved specific targeting of RANKL in vitro. PET imaging showed fast blood clearance and high tumor accumulation as early as 1 h p.i. (2.14 ± 0.21% ID/mL), which peaked at 5 h p.i. (2.72 ± 0.61% ID/mL). In contrast, [64Cu]Cu-NOTA-denosumab reached its highest tumor uptake at 24 h p.i. (6.88 ± 1.12% ID/mL). [64Cu]Cu-NOTA-denos-Fab specifically targeted human RANKL in transduced ME-180 xenografts compared with the blocking group and negative ME-180 xenograft model. Histological analysis confirmed RANKL expression in RANKL-ME-180 xenografts.ConclusionsHere, we report on a novel RANKL PET imaging agent, [64Cu]Cu-NOTA-denos-Fab, that allows for fast tumor imaging with improved imaging contrast when compared with its antibody counterpart, showing promise as a potential PET RANKL imaging tool for future clinical applications.

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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

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