Theranostics 2016; 6(4):511-521. doi:10.7150/thno.14261

Short Research Communication

Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89Zr4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice

Jeff N.Tinianow1*, Darpan N. Pandya2*, Sylvie L. Pailloux3, Annie Ogasawara1, Alexander N. Vanderbilt1, Herman S. Gill1, Simon-P. Williams1, Thaddeus J. Wadas2, Darren Magda3✉, Jan Marik1✉

1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
2. Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157.
3. Lumiphore, Inc. 600 Bancroft Way, Suite B Berkeley, CA 94710.
*These authors contributed equally to this work.

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Citation:
N.Tinianow J, Pandya DN, Pailloux SL, Ogasawara A, Vanderbilt AN, Gill HS, Williams SP, Wadas TJ, Magda D, Marik J. Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89Zr4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice. Theranostics 2016; 6(4):511-521. doi:10.7150/thno.14261. Available from http://www.thno.org/v06p0511.htm

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Abstract

A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of 89Zr; subsequently, it was used as a bi-functional chelator for preparation of 89Zr-labeled antibodies. Quantitative chelation of 89Zr4+ with the octadentate ligand forming 89ZrL complex was achieved under mild conditions within 15 minutes. The 89Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic 89Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of 89Zr4+ from the complex.

The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with 89Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of 89Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control 89Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g).

In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of 89Zr-labeled monoclonal antibodies for immunoPET studies.

Keywords: immunoPET, positron emission tomography, monoclonal antibody, imaging, 89Zr, radiolabeling, 2, 3-HOPO, 3-hydroxypyridin-2-one.