Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging

Varasteh, Zohreh; Velikyan, Irina; Lindeberg, Gunnar; Sörensen, Jens; Larhed, Mats; Sandström, Mattias; Selvaraju, Ram Kumar; Malmberg, Jennie; Tolmachev, Vladimir; Orlova, Anna

doi:10.1021/bc300659k

Cited by 67 publications

(127 citation statements)

References 38 publications

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“…Emerging functional imaging techniques, including diffusion-weighted MR imaging, dynamic contrastenhanced MR imaging, and PET, have shown improved sensitivity and staging accuracy for detecting primary prostate tumors and metastatic lymph nodes (3). Several PET radiotracers have shown promising clinical utility, such as the metabolic agents 18 F-FDG, 11 C-/ 18 F-choline, and 11 C-/ 18 F-acetate for the assessment of distant metastasis and 18 F-NaF for the detection of bone metastasis (4). However, their application is most valuable in late-stage, recurrent, or metastatic PCa.…”

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confidence: 99%

“…Several GRPR antagonists have since been developed by the modification of C-terminal residues of GRPR agonists, including the statinbased BBN analog, JMV594 (H-D-Phe-Gln-Trp-Ala-Val-GlyHis-Sta-Leu-NH 2 ) (15). 68 Ga-labeled GRPR antagonists were developed for PET imaging, showing good targeting properties in preclinical studies (12,(16)(17)(18) and recently also in clinical trials (19,20). Clinical evaluation of the 68 Ga-labeled GRPR antagonist BAY86-7548 ( 68 Ga-DOTA-4-amino-1-carboxymethylpiperidine-D-Phe-Gln-TrpAla-Val-Gly-His-Sta-Leu-NH 2 ) has shown a specificity, sensitivity, and accuracy of 88%, 81%, and 83%, respectively, for the detection of primary PCa.…”

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confidence: 99%

“…Therefore, the aim of the present study was to develop an 18 F-labeled GRPR antagonist for highresolution and sensitive PET imaging of primary, recurrent, and metastatic PCa and to compare the imaging properties of this tracer with those of 68 Ga-labeled analogs. 18 F has superior physical characteristics for PET imaging, such as a lower positron range and a higher positron yield, offering higher resolution and sensitivity (23). However, most methods for labeling peptides with 18 F are laborious and require multistep procedures with moderate labeling yields.…”

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Preclinical Comparison of Al¹⁸F- and ⁶⁸Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

et al. 2014

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International audienceGastrin-releasing peptide receptor (GRPR) is overexpressed in human prostate cancer and is being used as a target for molecular imaging. In this study, we report on the direct comparison of 3 novel GRPR-targeted radiolabeled tracers: Al18F-JMV5132, 68Ga-JMV5132, and 68Ga-JMV4168 (JMV5132 is NODA-MPAA-βAla-βAla-[H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], JMV4168 is DOTA-βAla-βAla-[H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2], and NODA-MPAA is 2-[4-(carboxymethyl)-7-{[4-(carboxymethyl)phenyl]methyl}-1,4,7-triazacyclononan-1-yl]acetic acid). Methods: The GRPR antagonist JMV594 (H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was conjugated to NODA-MPAA for labeling with Al18F. JMV5132 was radiolabeled with 68Ga and 18F, and JMV4168 was labeled with 68Ga for comparison. The inhibitory concentration of 50% values for binding GRPR of JMV4168, JMV5132, natGa-JMV4168, and natGa-JMV5132 were determined in a competition-binding assay using GRPR-overexpressing PC-3 tumors. The tumor-targeting characteristics of the compounds were assessed in mice bearing subcutaneous PC-3 xenografts. Small-animal PET/CT images were acquired, and tracer biodistribution was determined by ex vivo measurements. Results: JMV5132 was labeled with 18F in a novel 1-pot, 1-step procedure within 20 min, without need for further purification and resulting in a specific activity of 35 MBq/nmol. Inhibitory concentration of 50% values (in nM) for GRPR binding of JMV5132, JMV4168, natGa-JMV5132, natGa-JMV4168, and AlnatF-JMV5132 were 6.8 (95% confidence intervals [CIs], 4.6–10.0), 13.2 (95% CIs, 5.9–29.3), 3.0 (95% CIs, 1.5–6.0), 3.2 (95% CIs, 1.8–5.9), and 10.0 (95% CIs, 6.3–16.0), respectively. In mice with subcutaneous PC-3 xenografts, all tracers cleared rapidly from the blood, exclusively via the kidneys for 68Ga-JMV4168 and partially hepatobiliary for 68Ga-JMV5132 and Al18F-JMV5132. Two hours after injection, the uptake of 68Ga-JMV4168, 68Ga-JMV5132, and Al18F-JMV5132 in PC-3 tumors was 5.96 ± 1.39, 5.24 ± 0.29, 5.30 ± 0.98 (percentage injected dose per gram), respectively. GRPR specificity was confirmed by significantly reduced tumor uptake of the 3 tracers after coinjection of a 100-fold excess of unlabeled JMV4168 or JMV5132. Small-animal PET/CT clearly visualized PC-3 tumors, with the highest resolution observed for Al18F-JMV5132. Conclusion: JMV5132 could be rapidly and efficiently labeled with 18F. Al18F-JMV5132, 68Ga-JMV5132, and 68Ga-JMV4168 all showed comparable high and specific accumulation in GRPR-positive PC-3 tumors. These new PET tracers are promising candidates for future clinical translation

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Preclinical Comparison of Al¹⁸F- and ⁶⁸Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

et al. 2014

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“…In the first study, the binding of the pPYY peptide to cells expressing different degrees of the human neuropeptide receptor hY2R [15] was measured. In the second study, the interaction between the bombesin antagonist RM26 developed for medicinal imaging of cancer and the gastrin-releasing peptide receptor GRPR [16] was detected. The binding showed clear signs of interaction heterogeneity and was therefore further evaluated using Interaction Map.…”

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confidence: 99%

“…, Leu14] bombesin) [17] was synthesized and labeled with 111 In (Covidien, Dublin, Ireland) as described previously [16].…”

Section: Reagents and Labelingmentioning

confidence: 99%

Detecting ligand interactions with G protein-coupled receptors in real-time on living cells

Varasteh

Orlova

et al. 2013

Biochemical and Biophysical Research Communications

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G protein-coupled receptors (GPCRs) are a large group of receptors of great biological and clinical relevance. Despite this, the tools for a detailed analysis of ligand -GPCR interactions are limited. The aim of this paper was to demonstrate how ligand binding to GPCRs can be followed in real-time on living cells. This was conducted using two model systems, the radiolabeled porcine peptide YY (pPYY) interacting with transfected human Y2 receptor (hY2R) and the bombesin antagonist RM26 binding to the naturally expressed gastrin-releasing peptide receptor (GRPR). By following the interaction over time, the affinity and kinetic properties such as association and dissociation rate were obtained.Additionally, data were analyzed using the Interaction Map method, which can evaluate a real-time binding curve and present the number of parallel interactions contributing to the curve. It was found that pPYY binds very slowly with an estimated time to equilibrium of approximately 12 hours. This may be problematic in standard end-point assays where equilibrium is required. The RM26 binding showed signs of heterogeneity, observed as two parallel interactions with unique kinetic properties.In conclusion, measuring binding in real-time using living cells opens up for a better understanding of ligand interactions with GPCRs.

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Continued rapid growth in ⁶⁸Ga applications: update 2013 to June 2014

Velikyan

2015

Labelled Comp Radiopharmac

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The worldwide utilization of (68) Ga-radionuclide for the fundamental research and clinical applications is growing exponentially. A broad range of (68) Ga-based imaging agents has been explored during recent years. The development of new clinically useful agents is encouraged by many factors; for example, increasing role of positron emission tomography (PET) in nuclear medicine, discovery of new biomarkers, accessibility of (68) Ga, and establishment of PET radiopharmaceutical regulation and legislation. The focus of this review resides on the reports regarding (68) Ga-related research and applications published during 2013 to June 2014.

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Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging

Cited by 67 publications

References 38 publications

Preclinical Comparison of Al¹⁸F- and ⁶⁸Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

Preclinical Comparison of Al¹⁸F- and ⁶⁸Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

Detecting ligand interactions with G protein-coupled receptors in real-time on living cells

Continued rapid growth in ⁶⁸Ga applications: update 2013 to June 2014

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Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging

Cited by 67 publications

References 38 publications

Preclinical Comparison of Al18F- and 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

Preclinical Comparison of Al18F- and 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

Detecting ligand interactions with G protein-coupled receptors in real-time on living cells

Continued rapid growth in 68Ga applications: update 2013 to June 2014

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Preclinical Comparison of Al¹⁸F- and ⁶⁸Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

Preclinical Comparison of Al¹⁸F- and ⁶⁸Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

Continued rapid growth in ⁶⁸Ga applications: update 2013 to June 2014