Macrocycle‐Based Hydroxamate Ligands for Complexation and Immunoconjugation of ⁸⁹Zirconium for Positron Emission Tomography (PET) Imaging

Abstract

Four novel chelators (<b>L1</b>-<b>L4</b>) and their ⁸⁹zirconium complexes were prepared and compared with the ⁸⁹zirconium 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-<b>L4</b> complex showed similar stability to that of ⁸⁹Zr-DFO when incubated in either rat blood plasma or ethylenediaminetetraacetic acid challenge experiments. Positron imaging and biodistribution studies in mice showed that ⁸⁹Zr-<b>L4</b> had similar pharmacokinetic behavior to that of ⁸⁹Zr-DFO, with rapid renal elimination and low residual activity in background tissues. A bifunctional version of <b>L4</b> (<b>L5</b>) was synthesized and conjugated to trastuzumab; an anti-HER2/neu antibody. Immunopositron emission tomography imaging and biodistribution with ⁸⁹Zr-<b>L5</b>-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 of ⁸⁹Zr-DFO-trastuzumab.