title: 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.
abstract: A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of (89)Zr; subsequently, it was used as a bi-functional chelator for preparation of (89)Zr-labeled antibodies. Quantitative chelation of (89)Zr(4+) with the octadentate ligand forming (89)ZrL complex was achieved under mild conditions within 15 minutes. The (89)Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic (89)Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of (89)Zr(4+) 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 (89)Zr 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 (89)Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control (89)Zr-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 (89)Zr-labeled monoclonal antibodies for immunoPET studies.
authors.affiliation: 1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
authors.forename: Jeff
authors.initials: J
authors.lastname: N Tinianow
authors.affiliation: 2. Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157.
authors.forename: Darpan N
authors.initials: DN
authors.lastname: Pandya
authors.affiliation: 3. Lumiphore, Inc. 600 Bancroft Way, Suite B Berkeley, CA 94710.
authors.forename: Sylvie L
authors.initials: SL
authors.lastname: Pailloux
authors.affiliation: 1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
authors.forename: Annie
authors.initials: A
authors.lastname: Ogasawara
authors.affiliation: 1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Vanderbilt
authors.affiliation: 1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Gill
authors.affiliation: 1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
authors.forename: Simon-P
authors.initials: SP
authors.lastname: Williams
authors.affiliation: 2. Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157.
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Wadas
authors.affiliation: 3. Lumiphore, Inc. 600 Bancroft Way, Suite B Berkeley, CA 94710.
authors.forename: Darren
authors.initials: D
authors.lastname: Magda
authors.affiliation: 1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
authors.forename: Jan
authors.initials: J
authors.lastname: Marik
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography / Q000379:methods*; D011728:Pyridones / Q000008:administration & dosage*; D019275:Radiopharmaceuticals / Q000008:administration & dosage*; D015040:Zirconium / Q000008:administration & dosage*
chemical_list: D002614:Chelating Agents; D011728:Pyridones; D019275:Radiopharmaceuticals; C091598:3-hydroxypyridin-2-one; D015040:Zirconium
keywords: 2; 3-HOPO; 3-hydroxypyridin-2-one.; 89Zr; imaging; immunoPET; monoclonal antibody; positron emission tomography; radiolabeling