[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging αvβ3 integrin expression: synthesis, evaluation, and comparison

Knetsch, Peter A.; Petřík, Miloš; Rangger, C.; Seidel, Gesine; Pietzsch, Hans‐Jürgen; Virgolini, Irene; Decristoforo, Clemens; Haubner, Roland

doi:10.1016/j.nucmedbio.2012.09.006

Cited by 18 publications

(16 citation statements)

References 28 publications

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“…35 The fully protected, open peptide was cyclized using diphenylphosphorylazide (DPPA) and NaHCO 3 . 36 A mixture of the crude protected acyclic peptide (1 equiv, 90 μ mol, 100 mg), NaHCO 3 (5 equiv, 450 μ mol, 36 mg), DMF (100 mL), and DPPA (3 equiv, 270 μ mol, 80 mg) was stirred overnight. Upon confirming the completion of cyclization by ESI-MS, the solvent was evaporated under vacuum and deprotection was performed without purification using a mixture of TFA, H 2 O, and TES (95:2.5:2.5).…”

Section: Methodsmentioning

confidence: 99%

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

et al. 2014

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Differential expression of surface proteins on normal vs malignant cells provides the rationale for the development of receptor-, antigen-, and transporter-based, cancer-selective imaging and therapeutic agents. However, tumors are heterogeneous, and do not always express what can be considered reliable, tumor-selective markers. That suggests development of more flexible targeting platforms that incorporate multiple moieties enabling concurrent targeting to a variety of putative markers. We report the synthesis, biochemical, in vitro, and preliminary in vivo evaluation of a new heterobivalent (HtBv) imaging agent targeting both the prostate-specific membrane antigen (PSMA) and integrin-αvβ3 surface markers, each of which can be overexpressed in certain tumor epithelium and/or neovasculature. The HtBv agent was functionalized with either 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or the commercially available IRDye800CW. DOTA-conjugated HtBv probe 9 bound to PSMA or αvβ3 with affinities similar to those of monovalent (Mnv) compounds designed to bind to their targets independently. In situ energy minimization experiments support a model describing the conformations adapted by 9 that enable it to bind both targets. IRDye800-conjugated HtBv probe 10 demonstrated target-specific binding to either PSMA or integrin-αvβ3 overexpressing xenografts. HtBv agents 9 and 10 may enable dual-targeted imaging of malignant cells and tissues in an effort to address heterogeneity that confounds many cancer-targeted imaging agents.

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Section: Methodsmentioning

confidence: 99%

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

et al. 2014

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“…Although showing similar complexation characteristics, the oxo derivative did not inherit the advantage of kinetic inertness from the parent DOTA; however, p‐NO 2 ‐Bn‐PCTA shows both high kinetic inertness and favourable in vivo biodistribution characteristics. A study of the oxo derivative also shows inferior in vivo characteristics when conjugated to Arginylglycylaspartic acid (RGD) peptides . p‐NO 2 ‐Bn‐PCTA has subsequently been compared with a 1,4,7‐triazacyclononane‐1,4,7‐triacetic acid (NOTA) derivative for small peptide in vivo imaging and has been shown to have very similar properties, adding to the library of BFCs suitable for in vivo 68 Ga imaging …”

Section: Macrocyclic Chelatorsmentioning

confidence: 99%

Recent advances in chelator design and labelling methodology for ⁶⁸Ga radiopharmaceuticals

Burke

Clemente

Archibald

2014

Labelled Comp Radiopharmac

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Gallium-68 has the potential to become the technetium-99m of positron emission tomography with ideal decay characteristics and a long-lived parent isotope for generator production. The work in the area of (68) Ga is focused on two key areas: (1) synthesis of a library of bifunctional chelators, which can be quickly radiolabelled to form kinetically inert complexes under mild conditions compatible with biomolecules and (2) development of radiosynthetic methodologies for clinical use and to facilitate radiolabelling of a wide range of chelators under mild conditions. Recent advances in these areas, with particular focus on the past 3 years, are covered herein.

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“…Integrins a V b 3 have been shown to play an important role in a series of pathologic processes including angiogenesis and tumor cell metastasis (2,(13)(14)(15)(16)(17)(18). Given the high affinity of RGD-based peptides for a V b 3 integrin receptors, a variety of cyclic RGD peptide conjugates have been used to target tumors overexpressing these receptors (9)(10)(11)(12)(14)(15)(16)19,20). However, it has been demonstrated that the dimeric conjugate is more suitable, for both imaging and therapeutic applications, than the monomeric conjugate.…”

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confidence: 99%

“…Somatostatin analogs have been in use the longest, have led to the accumulation of a vast amount of data, and have proven useful for the management of patients with neuroendocrine tumors (4)(5)(6)(7)(8). Several other peptide receptorbinding compounds have been synthesized within the past few years and are currently in various research stages-in vitro, in vivo, and preclinical studies-but have not yet been approved for clinical use (9)(10)(11). These new and rapidly expanding peptide-based radiopharmaceuticals deserve close attention.…”

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confidence: 99%

“…Recently, several publications have reported on various radiolabeled RGD-containing peptides with high affinity and selectivity for a V b 3 integrin receptors both in vitro and in vivo in animal models (10,(14)(15)(16). Additionally, detailed biodistribution and measured radiation dosimetry in humans have been reported for 18 F-galactoRGD (26), 18 F-RGD-K5 (27), 68 Ga-NOTA-RGD (28), and 18 F-FPPRGD2 (29).…”

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PET-Based Human Dosimetry of the Dimeric α_vβ₃ Integrin Ligand ⁶⁸Ga-DOTA-E-[c(RGDfK)]₂, a Potential Tracer for Imaging Tumor Angiogenesis

et al. 2015

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Peptides containing the Arg-Gly-Asp (RGD) sequence have high affinity for α v β 3 integrin receptors overexpressed in tumor cells. The objective of this research was to determine the biodistribution and estimate the radiation dose from 68 Ga-DOTA-E-[c(RGDfK)] 2 using whole-body PET scans in humans. Methods: Five healthy volunteers (2 women, 3 men; mean age ± SD, 37.2 ± 15.6 y; range, 28-65 y; mean weight, 79.2 ± 21.0 kg; range, 64-115 kg) were included. After intravenous injection of the tracer (198.3 ± 3.3 MBq), 3 successive whole-body (vertex to mid thigh) PET/CT scans at 3 time points (30, 60, and 120 min) were obtained on a 16-slice PET/CT scanner. The subjects did not void the bladder until the entire series of images was completed. Low-dose CT without contrast agent was used for anatomic localization and attenuation correction. OLINDA/ EXM software was applied to calculate human radiation doses using the reference adult model. Results: The highest uptake was in the urinary bladder, followed by the liver, kidneys, and spleen, in descending order. The critical organ was the urinary bladder wall. The mean effective doses (all subjects, men and women) were 34.1 ± 4.9, 31.0 ± 2.4, and 20.9 ± 5.2 μSv/MBq for the no-voiding, 2.5-h-voiding, and 1-h-voiding models, respectively. Conclusion: Of particular interest in this research was the visualization of the choroid plexus and ventricular system, which seems to be a characteristic of RGD-dimeric peptides. Measured absorbed doses and effective doses are comparable to other previously reported RGD-based radiopharmaceuticals labeled with 68 Ga and 18 F. Therefore, 68 Ga-DOTA-E-[c(RGDfK)] 2 can safely be used for imaging integrin α V β 3 expression. The last few years have witnessed the development of a virtual revolution in PET molecular imaging, and radiolabeled receptor-binding peptides are emerging as powerful tools for imaging and therapy applications of tumors expressing peptide binding receptors (1-3). Somatostatin analogs have been in use the longest, have led to the accumulation of a vast amount of data, and have proven useful for the management of patients with neuroendocrine tumors (4-8). Several other peptide receptorbinding compounds have been synthesized within the past few years and are currently in various research stages-in vitro, in vivo, and preclinical studies-but have not yet been approved for clinical use (9-11). These new and rapidly expanding peptide-based radiopharmaceuticals deserve close attention.It has been shown that peptides based on the RGD amino acid sequence have a high affinity and selectivity for a V b 3 integrin receptors (12). The a V b 3 integrins are transmembrane proteins that are preferentially expressed on proliferating endothelial cells but absent from quiescent endothelial cells (13). Integrins are overexpressed on newly formed blood vessels of actively growing tumors and are therefore potential targets for receptor-mediated tumor imaging and therapy when labeled with the proper radionuclide. Angiogenesis, the formation of n...

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[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging αvβ3 integrin expression: synthesis, evaluation, and comparison

Cited by 18 publications

References 28 publications

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

Recent advances in chelator design and labelling methodology for ⁶⁸Ga radiopharmaceuticals

PET-Based Human Dosimetry of the Dimeric α_vβ₃ Integrin Ligand ⁶⁸Ga-DOTA-E-[c(RGDfK)]₂, a Potential Tracer for Imaging Tumor Angiogenesis

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[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging αvβ3 integrin expression: synthesis, evaluation, and comparison

Cited by 18 publications

References 28 publications

Heterobivalent Agents Targeting PSMA and Integrin-αvβ3

Heterobivalent Agents Targeting PSMA and Integrin-αvβ3

Recent advances in chelator design and labelling methodology for 68Ga radiopharmaceuticals

PET-Based Human Dosimetry of the Dimeric αvβ3 Integrin Ligand 68Ga-DOTA-E-[c(RGDfK)]2, a Potential Tracer for Imaging Tumor Angiogenesis

Contact Info

Product

Resources

About

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

Heterobivalent Agents Targeting PSMA and Integrin-α_vβ₃

Recent advances in chelator design and labelling methodology for ⁶⁸Ga radiopharmaceuticals

PET-Based Human Dosimetry of the Dimeric α_vβ₃ Integrin Ligand ⁶⁸Ga-DOTA-E-[c(RGDfK)]₂, a Potential Tracer for Imaging Tumor Angiogenesis