Synthesis and characterization of lipophilic cationic Ga(III) complexes based on the H2CHXdedpa and H2dedpa ligands and their 67/68Ga radiolabeling studies

68Ga is an attractive isotope for incorporation into a positron-emission tomography (PET) imaging agent{,} and is finding use as an alternative generator-produced isotope to 99mTc particularly in imaging of myocardial perfusion. We have synthesized six new chelating ligands based on our previously reported H2dedpa and H2CHXdedpa scaffolds (CHX = cyclohexyl{,} H2dedpa = 1{,}2-[[carboxypyridin-2-yl]methylamino]ethane). These ligands are designed to incorporate several lipophilic appendages at the secondary nitrogens{,} and upon coordination to 68Ga(iii) will form lipophilic{,} cationic complexes designed to mimic the properties of other clinically relevant myocardial perfusion imaging agents. The non-radioactive Ga(iii) complexes were prepared and characterized by NMR spectroscopy; each ligand retained its predicted hexadentate N4O2 binding to Ga(iii). The radiolabeling properties of the six ligands were assessed using the longer-lived 68Ga surrogate{,} 67Ga. The absence of {'}free{'} uncomplexed 67Ga in the HPLC radio-chromatograms indicated >99% radiochemical yields (10 minutes at ambient temperature{,} ligand concentrations of 10-4 M). However{,} the N{,}N[prime or minute]-benzyl functionalized derivatives displayed multiple peaks corresponding to the presence of additional 67Ga-complexes which complicated further study. Selected 67Ga-CHXdedpa complexes were tested for in vitro stability against the metal-binding protein apo-transferrin{,} and were found to be sufficiently stable (>80%) in a 2 h challenge assay{,} suggesting that alternative N{,}N[prime or minute]-alkylated derivatives which introduce more lipophilic character will be of interest in future studies.