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

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