A highly effective bifunctional ligand for radioimmunotherapy applications

Chong, Hyun‐Soon; Song, Hyun Beom; Kang, Chi Soo; Le, Thien; Sun, Xiang; Dadwal, Mamta; Lee, Hyunbeom; Lan, Xiaoli; Chen, Yunwei; Dai, Anzhi

doi:10.1039/c0cc05707j

Cited by 29 publications

(53 citation statements)

References 19 publications

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“…Bisubstituted 1,4,7-triazacyclononane (TACN) analogue 1 12 was reacted with an alkylating agent 2 15 and 4 11 to provide the key precursor molecules 3 and 5 , respectively. Removal of tert-butyl groups in 3 and 5 was accomplished by treatment of 3 and 5 with HCl (aq) to afford the respective bifunctional chelators A 16 and B .…”

Section: Resultsmentioning

confidence: 99%

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

Sin

Kang

Bandara

et al. 2014

Bioorganic & Medicinal Chemistry

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A series of new hexadentate and pentadentate chelators were designed and synthesized as chelators of 64Cu. 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 64Cu. The new chelators instantly bound to 64Cu with high labeling efficiency and maximum specific activity. All 64Cu-radiolabeled complexes in human serum remained intact for 2 days. The 64Cu-radiolabeled complexes were further challenged by EDTA in a 100-fold molar excess. Among the 64Cu-radiolabeled complexes evaluated, 64Cu-complex of the new chelator E was well tolerated with a minimal transfer of 64Cu to EDTA. 64Cu-radiolabeled complex of the new chelator E was further evaluated for biodistribution studies using mice and displayed rapid blood clearance and low organ uptake. 64Cu-chelator E produced a favorable in vitro and in vivo complex stability profiles comparable to 64Cu 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.

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Section: Resultsmentioning

confidence: 99%

“…To a solution of 1 12 (72 mg, 0.29 mmol) in CH 3 CN (2 mL) at 0 °C was added dropwise 4 11 (105 mg, 0.29 mmol) in CH 3 CN (1 mL) and DIPEA (112 mg, 0.87 mmol). The resulting mixture was stirred for 61 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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

Sin

Kang

Bandara

et al. 2014

Bioorganic & Medicinal Chemistry

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“…To a stirred solution of 5 16 (1.60 g, 7.13 mmol) in 1,2-dichloroethane (40 mL) was added 2,4-dimethoxy-benzaldehyde (1.19 g, 7.13 mmol). The resulting solution was stirred for 10 min, and sodium triacetoxyborohydride (2.12 g, 9.99 mmol) was added portionwise to the solution over 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…A solution of diethyl malonate (1.04 g, 6.47 mmol) in THF (10 mL) was added dropwise over 10 min at 0 °C, and the reaction mixture was stirred for 30 min. To the reaction mixture was added dropwise a solution of 16 16 (1.58 g, 6.47 mmol) in THF (10 mL) over 10 min. The reaction was warmed to room temperature and stirred for 1 d. The reaction mixture was quenched by H 2 O (10 mL) and evaporated to dryness.…”

Section: Methodsmentioning

confidence: 99%

“…The new bifunctional chelates 3p- C -DE4TA ( 1 ) and 3p- C -NE3TA ( 2 ) and 3p- C -NOTA ( 3 ) were designed for evaluation of complexation with 90 Y and 177 Lu (Figure 1). The known bimodal chelates decadentate 3p- C -DEPA ( 4 ) 17 and octadentate 3p- C -NETA ( 5 ) 16 were also evaluated for complexation with 90 Y and 177 Lu for comparison. The comparative evaluation of the bimodal chelates with the structural variations is expected to advance our understanding on effect of the coordination factors including bimodality, denticity, and macrocyclic cavity on complexation of the bimodal chelates with the β-emitting radiolanthanides.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of 90Y and 177Lu

Chong

Sun

Chen

et al. 2015

Bioorganic & Medicinal Chemistry

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Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope (90Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin’s lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides 90Y and 177Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with 90Y and 177Lu, and the corresponding 90Y or 177Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding 90Y and 177Lu, and the corresponding 90Y- and 177Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of 90Y and 177Lu.

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A thiopyrylium salt for PET/NIR‐II tumor imaging and image‐guided surgery

Zhang

Ding

et al. 2020

Molecular Oncology

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All tumor imaging modalities have resolution limits below which deeply situated small metastatic foci may not be identified. Moreover, incomplete lesion excision will affect the outcomes of the patients. Scintigraphy is adept in locating lesions, and second near-infrared window (NIR-II) imaging may allow precise real-time tumor delineation. To achieve complete excision of all lesions, multimodality imaging is a promising method for tumor identification and management. Here, a NIR-II thiopyrylium salt, XB1034, was first synthesized and bound to cetuximab and trans-cyclooctene (TCO) to produce XB1034-cetuximab-TCO. This probe provides excellent sensitivity and high temporal resolution NIR-II imaging in mice bearing tumors developed from human breast cancer cells MDA-MB-231. To enable PET imaging, 68 Ga-NETA-tetrazine is subsequently injected into the mice to undergo a bio-orthogonal reaction with the preinjected XB1034-cetuximab-TCO. PET images achieved in the tumor models using the pretargeting strategy are of much higher quality than those obtained using the direct radiolabeling method. Moreover, real-time NIR-II imaging allows accurate tumor excision and sentinel lymph node mapping. In conclusion, XB1034 is a promising molecular imaging probe for tumor diagnosis and treatment.Abbreviations DCE, dichloroethane; EGFR, epidermal growth factor receptor; H&E, hematoxylin and eosin; HOMOs, highest occupied molecular orbitals; HPLC, high-performance liquid chromatography; ICG, indocyanine green; LP, long pass; LUMOs, lowest unoccupied molecular orbitals; MALDI-TOF MS, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; MTT, methyl thiazolyl tetrazolium; NETA-Tz, tetrazine-(2,2 0 -((6-amino-1-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)hexan-2-yl)azanediyl)diacetic acid; NIR-II, second near-infrared window;

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A highly effective bifunctional ligand for radioimmunotherapy applications

Cited by 29 publications

References 19 publications

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

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

Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of 90Y and 177Lu

A thiopyrylium salt for PET/NIR‐II tumor imaging and image‐guided surgery

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