title: Macrocycle-Based Hydroxamate Ligands for Complexation and Immunoconjugation of89Zirconium for Positron Emission Tomography (PET) Imaging.
abstract: Four novel chelators (L1-L4) and their89zirconium complexes were prepared and compared with the89zirconium desferrioxamine B (DFO) complex. The new chelates are based on 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) scaffolds and present either three or four hydroxamate arms for coordination with Zr4+ions with coordination numbers between six and eight. The 89Zr-L4complex showed similar stability to that of89Zr-DFO when incubated in either rat blood plasma or ethylenediaminetetraacetic acid challenge experiments. Positron imaging and biodistribution studies in mice showed that89Zr-L4had similar pharmacokinetic behavior to that of89Zr-DFO, with rapid renal elimination and low residual activity in background tissues. A bifunctional version ofL4(L5) was synthesized and conjugated to trastuzumab; an anti-HER2/neu antibody. Immunopositron emission tomography imaging and biodistribution with89Zr-L5-trastuzumab revealed high tumor to background ratios (tumor/blood ratio: 14.2 ± 2.25) and a high tumor specificity that was comparable to the performance of89Zr-DFO-trastuzumab.
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging Department of Radiology, Massachusetts General Hospital Harvard Medical School, 149 Thirteenth Street, Suite 2301 Charlestown, MA 02129 (USA).
authors.forename: Eszter
authors.initials: E
authors.lastname: Boros
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital, Department of Radiology Harvard Medical School, 55 Fruit Street, White 427 Boston, MA 02114 (USA).
authors.forename: Jason P
authors.initials: JP
authors.lastname: Holland
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging Department of Radiology, Massachusetts General Hospital Harvard Medical School, 149 Thirteenth Street, Suite 2301 Charlestown, MA 02129 (USA).
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Kenton
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging Department of Radiology, Massachusetts General Hospital Harvard Medical School, 149 Thirteenth Street, Suite 2301 Charlestown, MA 02129 (USA).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rotile
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging Department of Radiology, Massachusetts General Hospital Harvard Medical School, 149 Thirteenth Street, Suite 2301 Charlestown, MA 02129 (USA).
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
keywords: antitumor agents; imaging agents; macrocycles; radiopharmaceuticals; zirconium