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Title: p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for 89Zr ImmunoPET

Journal Article · · Bioconjugate Chemistry
 [1];  [2];  [2];  [3];  [3];  [4];  [5];  [6]
  1. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology and the Program in Molecular Pharmacology; City Univ. (CUNY), NY (United States). Hunter College, Dept. of Chemistry; City Univ. (CUNY), NY (United States). Dept. of Chemistry
  2. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology and the Program in Molecular Pharmacology; City Univ. (CUNY), NY (United States). Hunter College, Dept. of Chemistry
  3. City Univ. (CUNY), NY (United States). Hunter College, Dept. of Chemistry
  4. New York Univ. (NYU), NY (United States). Dept. of Chemistry
  5. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology and the Program in Molecular Pharmacology
  6. City Univ. (CUNY), NY (United States). Hunter College, Dept. of Chemistry; City Univ. (CUNY), NY (United States). Dept. of Chemistry
+ Show Author Affiliations

Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the 89Zr4+ cation is being released in vivo. Therefore, a more robust chelator for 89Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of 89Zr4+ and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. p-SCN-Bn-HOPO was synthesized through a novel pathway. Both p-SCN-Bn-HOPO and p-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with 89Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (n = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the 89Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for 89Zr-DFO-trastuzumab while 89Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized p-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for 89Zr. In vivo studies demonstrate the successful use of 89Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with 89Zr-HOPO-trastuzumab suggests superior stability of the 89Zr-HOPO complex.

Research Organization:
Sloan-Kettering Inst. for Cancer Research, New York, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
SC0002184; FG02-09ER16097
OSTI ID:
1467467
Journal Information:
Bioconjugate Chemistry, Vol. 26, Issue 12; ISSN 1043-1802
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 83 works
Citation information provided by
Web of Science

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Cited By (17)

Reassembly of 89 Zr‐Labeled Cancer Cell Membranes into Multicompartment Membrane‐Derived Liposomes for PET‐Trackable Tumor‐Targeted Theranostics journal February 2018
Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development journal January 2017
Improved synthesis of the bifunctional chelator p -SCN-Bn-HOPO journal January 2019
Combinatorial design of multimeric chelating peptoids for selective metal coordination journal January 2019
Inducing selectivity and chirality in group IV metal coordination with high-denticity hydroxypyridinones journal January 2019
Chemical aspects of metal ion chelation in the synthesis and application antibody-based radiotracers journal March 2018
Ultra-selective ligand-driven separation of strategic actinides journal June 2019
A comprehensively revised strategy that improves the specific activity and long-term stability of clinically relevant 89 Zr-immuno-PET agents journal January 2018
Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68 journal January 2017
Investigation of the complexation of nat Zr( iv ) and 89 Zr( iv ) by hydroxypyridinones for the development of chelators for PET imaging applications journal January 2017
Toxic heavy metal – Pb, Cd, Sn – complexation by the octadentate hydroxypyridinonate ligand archetype 3,4,3-LI(1,2-HOPO) journal January 2018
Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET journal June 2019
Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development text January 2017
Chemical aspects of metal ion chelation in the synthesis and application antibody-based radiotracers text January 2018
Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET journal August 2016
89 Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89 Zr Radiochemistry journal August 2017
Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89 Zr 4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice journal January 2016

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