Preparation and Biological Evaluation of <sup>64</sup>Cu-CB-TE2A-sst<sub>2</sub>-ANT, a Somatostatin Antagonist for PET Imaging of Somatostatin Receptor–Positive Tumors

Wadas, Thaddeus J.; Eiblmaier, Martin; Zheleznyak, Alexander; Sherman, Christopher D.; Ferdani, Riccardo; Liang, Kexian; Achilefu, Samuel; Anderson, Carolyn J.

doi:10.2967/jnumed.108.054502

Cited by 73 publications

(81 citation statements)

References 22 publications

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“…Innovative developments using agonists hybridized with other targeting units such as a v b 3 integrins or hypoxia-targeting agents such as 2-nitroimidazoles (25). The successful pharmacokinetic performance of somatostatin-based antagonistic radiotracers preclinically (6,26,27) and clinically (28) led several research groups to develop GRPr antagonists, which indeed exhibit pharmacokinetics superior to agonists (7)(8)(9)(10)(29)(30)(31)(32). Despite these promising data with the first antagonists, there is no consensus that antagonists are superior to agonists targeting the GRPr (33,34).…”

Section: Discussionmentioning

confidence: 99%

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of ⁶⁸Ga- and ⁶⁴Cu-Labeled Peptides for PET Imaging

et al. 2014

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Gastrin-releasing peptide receptors (GRPrs) are overexpressed on a variety of human cancers, providing the opportunity for peptide receptor targeting via radiolabeled bombesin-based peptides. As part of our ongoing investigations into the development of improved GRPr antagonists, this study aimed at verifying whether and how Nterminal modulations improve the affinity and pharmacokinetics of radiolabeled GRPr antagonists. Methods: The potent GRPr antagonist MJ9, Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 (Pip, 4-amino-1-carboxymethyl-piperidine), was conjugated to 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA), and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and radiolabeled with 68 Ga and 64 Cu. The GRPr affinity of the corresponding metalloconjugates was determined using 125 I-Tyr 4 -BN as a radioligand. The labeling efficiency of 68 Ga 31 was compared between NODAGA-MJ9 and NOTA-MJ9 in acetate buffer, at room temperature and at 95°C. The 68 Ga and 64 Cu conjugates were further evaluated in vivo in PC3 tumor xenografts by biodistribution and PET imaging studies. Results: The half maximum inhibitory concentrations of all the metalloconjugates are in the high picomolar-low nanomolar range, and these are the most affine-radiolabeled GRPr antagonists we have studied so far in our laboratory. NODAGA-MJ9 incorporates 68 Ga 31 nearly quantitatively (.98%) at room temperature within 10 min and at much lower peptide concentrations (1.4 · 10 −6 M) than NOTA-MJ9, for which the labeling yield was approximately 45% under the same conditions and increased to 75% at 95°C for 5 min. Biodistribution studies showed high and specific tumor uptake, with a maximum of 23.3 ± 2.0 percentage injected activity per gram of tissue (%IA/g) for 68 Ga-NOTA-MJ9 and 16.7 ± 2.0 %IA/g for 68 Ga-NODAGA-MJ9 at 1 h after injection. The acquisition of PET images with the 64 Cu-MJ9 conjugates at later time points clearly showed the efficient clearance of the accumulated activity from the background already at 4 h after injection, whereas tumor uptake still remained high. The high pancreas uptake for all radiotracers at 1 h after injection was rapidly washed out, resulting in an increased tumor-to-pancreas ratio at later time points. Conclusion: We have developed 2 GRPr antagonistic radioligands, which are improved in terms of binding affinity and overall biodistribution profile. Their promising in vivo pharmacokinetic performance may contribute to the improvement of the diagnostic imaging of tumors overexpressing GRPr.

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Section: Discussionmentioning

confidence: 99%

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of ⁶⁸Ga- and ⁶⁴Cu-Labeled Peptides for PET Imaging

et al. 2014

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“…Similar kidney retention of peptides with 64 Cu-labeled azamacrocycles, including that of 64 Cu-CB-TE2A-Y3-TATE and 64 Cu-CB-TE2A-somatostatin receptor subtype 2 selective antagonist (sst2-ANT), was previously reported. 25,45 Recent studies indicated that administering albumin fragments could reduce the renal uptake of radiolabeled peptides. 33 Since only a small fraction of total albumin passes through the glomerular membrane, it was hypothesized that the use of albumin fragments could competitively inhibit the uptake of radiolabeled peptides in the kidneys.…”

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confidence: 99%

In VitroandIn VivoEvaluation of⁶⁴Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas

Kumar

Gallazzi

Ferdani

et al. 2010

Cancer Biotherapy and Radiopharmaceuticals

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Epidermal growth factor receptor-2 (EGFR-2) has been implicated in the pathogenesis of breast and other carcinomas. In this report, we tested the ability of a bacteriophage selected peptide KCCYSL, radiolabeled with 64 Cu, to image EGFR-2 expressing breast tumors in vivo by positron emission tomography (PET). We evaluated and compared the in vivo tissue distribution and imaging properties of 64 Cu-X-(Gly-Ser-Gly)-KCCYSL peptide (X ¼ 1,4,7,10, tetraazacyclododecane-N,N',N'',N'''-tetracetic acid, [DOTA] 1,4,8, hexadecane-4,11-diacetic acid [CB-TE2A], and 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA] chelators) in a human breast cancer xenograft mouse model using dual modality PET and computed tomography (CT). The synthesized peptides DO3A-GSG-KCCYSL, CB-TE2A-GSG-KCCYSL, and NO2A-GSG-KCCYSL were purified, radiolabeled with 64 Cu, and evaluated for human breast cancer cell (MDA-MB-435) binding, 50% inhibitory concentration, and serum stability. In vivo pharmacokinetic and small animal PET/CT imaging studies were performed using SCID mice bearing MDA-MB-435 xenografts. The radiolabeled peptides bound with an 50% inhibitory concentration of 42.0 AE 10.2 nM (DO3A), 31 AE 7.9 nM (CB-TE2A), and 44.2 AE 6.6 nM (NO2A) to cultured MDA-MB-435 cells. All of the radiolabeled peptides were stable in vitro. The tumor uptake of DO3A, CB-TE2A, and NO2A peptides were 0.73 AE 0.15 percent injected dose per gram (%ID/g), 0.64 AE 0.08%ID/g, and 0.52 AE 0.04%ID/g, respectively at 1 hour. Liver uptake for the 64 Cu-DO3A-peptide (1.68 AE 0.42%ID/g) was more than that of the 64 Cu-CB-TE2A-peptide (0.52 AE 0.02% ID/g) and 64 Cu-NO2A-peptide (0.48 AE 0.05%ID/g) at 2 hours. PET/CT studies revealed successful tumor uptake of 64 Cu-peptides at 2 hours postinjection. In vivo kidney retention was observed with all of the radiolabeled peptides. The optimization of bifunctional chelators improves the pharmacokinetic properties of the 64 Cu-labeled GSG-KCCYSL peptide, which enables the selection of a suitable peptide homolog as a PET imaging agent for EGFR-2 expressing breast carcinomas.

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“…Radioligands for Imaging the Sigma-2 (σ 2 ) Receptor σ 2 receptors as a biomarker of proliferation in solid tumors were reported 10 years ago [141], and became a target for tumor diagnosis and treatment [142]. σ 2 receptors are expressed in proliferating tumor cells at a level about ten times higher than in quiescent tumor cells [141,143].…”

Section: Pet Probes For Imaging Somatostatin Receptorsmentioning

confidence: 99%

“…σ 2 receptors are expressed in proliferating tumor cells at a level about ten times higher than in quiescent tumor cells [141,143]. In pursuing imaging proliferation, benzamide radioligands with σ 2 receptor specificity were reported as PET tracers.…”

Section: Pet Probes For Imaging Somatostatin Receptorsmentioning

confidence: 99%

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

Zhu

Shim

2011

Nucl Med Mol Imaging

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Molecular imaging is one of the fastest growing areas of medical imaging. Positron emission tomography (PET) has been widely used in the clinical management of patients with cancer. Nuclear imaging provides biological information at the cellular, subcellular, and molecular level in living subjects with noninvasive procedures. In particular, PET imaging takes advantage of traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of cancer. 18 F-fluorodeoxyglucose ( 18 F-FDG), the only FDA approved oncological PET tracer, has been widely utilized in cancer diagnosis, staging, restaging, and even monitoring response to therapy; however, 18 F-FDG is not a tumor-specific PET tracer. Over the last decade, many promising tumor-specific PET tracers have been developed and evaluated in preclinical and clinical studies. This review provides an overview of the current non-18 F-FDG PET tracers in oncology that have been developed based on tumor characteristics such as increased metabolism, hyperproliferation, angiogenesis, hypoxia, apoptosis, and tumor-specific antigens and surface receptors.

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Preparation and Biological Evaluation of ⁶⁴Cu-CB-TE2A-sst₂-ANT, a Somatostatin Antagonist for PET Imaging of Somatostatin Receptor–Positive Tumors

Cited by 73 publications

References 22 publications

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of ⁶⁸Ga- and ⁶⁴Cu-Labeled Peptides for PET Imaging

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of ⁶⁸Ga- and ⁶⁴Cu-Labeled Peptides for PET Imaging

In VitroandIn VivoEvaluation of⁶⁴Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

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Preparation and Biological Evaluation of 64Cu-CB-TE2A-sst2-ANT, a Somatostatin Antagonist for PET Imaging of Somatostatin Receptor–Positive Tumors

Cited by 73 publications

References 22 publications

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of 68Ga- and 64Cu-Labeled Peptides for PET Imaging

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of 68Ga- and 64Cu-Labeled Peptides for PET Imaging

In VitroandIn VivoEvaluation of64Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

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Preparation and Biological Evaluation of ⁶⁴Cu-CB-TE2A-sst₂-ANT, a Somatostatin Antagonist for PET Imaging of Somatostatin Receptor–Positive Tumors

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of ⁶⁸Ga- and ⁶⁴Cu-Labeled Peptides for PET Imaging

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of ⁶⁸Ga- and ⁶⁴Cu-Labeled Peptides for PET Imaging

In VitroandIn VivoEvaluation of⁶⁴Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas