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Novel hexadentate and pentadentate chelators for ??Cu-based targeted PET imaging.

ABSTRACT: A series of new hexadentate and pentadentate chelators were designed and synthesized as chelators of (64)Cu. The new pentadentate and hexadentate chelators contain different types of donor groups and are expected to form neutral complexes with Cu(II). The new chelators were evaluated for complex kinetics and stability with (64)Cu. The new chelators instantly bound to (64)Cu with high labeling efficiency and maximum specific activity. All (64)Cu-radiolabeled complexes in human serum remained intact for 2 days. The (64)Cu-radiolabeled complexes were further challenged by EDTA in a 100-fold molar excess. Among the (64)Cu-radiolabeled complexes evaluated, (64)Cu-complex of the new chelator E was well tolerated with a minimal transfer of (64)Cu to EDTA. (64)Cu-radiolabeled complex of the new chelator E was further evaluated for biodistribution studies using mice and displayed rapid blood clearance and low organ uptake. (64)Cu-chelator E produced a favorable in vitro and in vivo complex stability profiles comparable to (64)Cu complex of the known hexadentate NOTA chelator. The in vitro and in vivo data highlight strong potential of the new chelator E for targeted PET imaging application.

SUBMITTER: Sin I

PROVIDER: S-EPMC4139964 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Novel hexadentate and pentadentate chelators for ⁶⁴Cu-based targeted PET imaging.

Sin Inseok I Kang Chi Soo CS Bandara Nilantha N Sun Xiang X Zhong Yongliang Y Rogers Buck E BE Chong Hyun-Soon HS

Bioorganic & medicinal chemistry 20140301 8

A series of new hexadentate and pentadentate chelators were designed and synthesized as chelators of (64)Cu. The new pentadentate and hexadentate chelators contain different types of donor groups and are expected to form neutral complexes with Cu(II). The new chelators were evaluated for complex kinetics and stability with (64)Cu. The new chelators instantly bound to (64)Cu with high labeling efficiency and maximum specific activity. All (64)Cu-radiolabeled complexes in human serum remained inta ...[more]

PMID: 24657050

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Project description:Background: The tumor-associated disialoganglioside GD2 is a bona fide immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease. Therefore, a non-invasive approach for the assessment and visualization of GD2 expression in-vivo is of upmost interest and might enable a more appropriate treatment stratification. Methods: Recently, [64Cu]Cu-NOTA-ch14.18/CHO (64Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed. We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with 64Cu-GD2 PET/MRI. GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6). Results: In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased 64Cu-GD2 uptake and a high tracer uptake (SUVmax > 10) was measured in 4 of those 8 patients. Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1. In case of 64Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys. Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients. Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04). Conclusion: 64Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.

Dataset Information

Novel hexadentate and pentadentate chelators for ??Cu-based targeted PET imaging.

Publications

Novel hexadentate and pentadentate chelators for ⁶⁴Cu-based targeted PET imaging.

Similar Datasets

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