Effects of targeting moiety, linker, bifunctional chelator, and molecular charge on biological properties of 64Cu-labeled triphenylphosphonium cations

In this report, we present the synthesis and evaluation of six new Cu-64-labeled triphenylphosphonium (TPP) cations. Biodistribution studies were performed using the athymic nude mice bearing U87MG human glioma xenografts to explore the impact of TPP moieties, linkers, bifunctional chelators (BFCs), and molecular charge on biological properties of Cu-64 radiotracers. On the basis of the results from this study, it is concluded that (1) mTPP (tris(4-methoxyphenyl)phosphonium) is a better mitochondrion-targeting molecule than TPP and 3mTPP (tris(2,4,6-trimethoxyphenyl)phosphonium); (2) DO3A (1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid) and DO2A (1,4,7, 10-tetraazacyclododecane-4,7-diacetic acid) are suitable BFCs for the Cu-64-labeling of TPP cations; (3) NOTA-Bn (S-2-(4-thioureidobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid) has a significant adverse effect on the radiotracer tumor uptake and tumor-to-background ratios; and (4) monoanionic BFCs should be avoided to ensure that Cu-64 chelate has a neutral or negative charge. Considering the tumor uptake and tumor/liver ratios, Cu-64(DO2A-xy-TPP)(+) is the best candidate for more extensive evaluations in different tumor-bearing animal models.