Synthesis and Evaluation of New Generation Cross-Bridged Bifunctional Chelator for ⁶⁴Cu Radiotracers

Abstract

Bifunctional chelators have been successfully used to construct (64)Cu-labeled radiopharmaceuticals. Previously reported chelators with cross-bridged cyclam backbones have various essential features such as high stability of the copper(II) complex, high efficiency of radiolabeling at room temperature, and good biological inertness of the radiolabeled complex, along with rapid body clearance. Here, we report a new generation propylene-cross-bridged chelator with hybrid acetate/phosphonate pendant groups (PCB-TE1A1P) developed with the aim of combining these key properties in a single chelator. The PCB-TE1A1P was synthesized from cyclam with good overall yield. The Cu(II) complex of our chelator showed good robustness in kinetic stability evaluation experiments, such as acidic decomplexation and cyclic voltammetry studies. The Cu(II) complex of PCB-TE1A1P remained intact under highly acidic conditions (12 M HCl, 90 °C) for 8 d and showed quasi-reversible reduction/oxidation peaks at -0.77 V in electrochemical studies. PCB-TE1A1P was successfully radiolabeled with (64)Cu ions in an acetate buffer at 60 °C within 60 min. The electrophoresis study revealed that the (64)Cu-PCB-TE1A1P complex has net negative charge in aqueous solution. The biodistribution and in vivo stability study profiles of (64)Cu-PCB-TE1A1P indicated that the radioactive complex was stable under physiological conditions and cleared rapidly from the body. A whole body positron emission tomography (PET) imaging study further confirmed high in vivo stability and fast clearance of the complex in mouse models. In conclusion, PCB-TE1A1P has good potential as a bifunctional chelator for (64)Cu-based radiopharmaceuticals, especially those involving peptides.

A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and 64Cu Labeling

“…Faster complexation is observed with N-phosphonic acid analogues, although heating is still necessary for the moment. 49,50,51,52 New linear systems such as H 2 DEDPA and H2AZAPA 53,54 as well as other type of macrocyclic ligands and cages (DiamSar 55,56,57 and its derivatives) offer good radiolabelling conditions at room temperature (Chart 2) and for some of them, a high degree of kinetic inertness. Bispidine derivatives (L 4 and L 5 , Chart 2) also form particularly stable Cu (II) complexes in vitro and in vivo.…”

Current advances in ligand design for inorganic positron emission tomography tracers 68Ga, 64Cu, 89Zr and 44Sc

“…This may be due to the relatively low copper concentration under radiolabelling conditions, or due to the formation of hydroxyl radicals by radiolysis which would not be present during "cold" complexation (Table 8). 122,123 3.2.2. Whilst the chelate required less than 5 minutes to achieve 100% radiolabelling, the peptide conjugate was 100% labelled in 30 minutes.…”

New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology

“…A new generation of propylene-cross-bridged chelators with hybrid acetate/phosphonate pendant groups (PCB-TE1A1P) ( Figure 4 ) has been developed to improve the in vivo stability and fast clearance. PET analysis in mice confirmed that PCB-TE1A1P has good potential as a bifunctional chelator for 64 Cu-based radiopharmaceuticals, especially those based on peptides [ 109 ].…”