Radiolabeled organic
cations, such as
triphenylphosphonium (TPP), represents a new class of radiotracers for imaging
cancers and the transport function of multidrug resistance
P-glycoproteins (particularly MDR1 Pgp) by single photon emission computed tomography (SPECT) or positron emission tomography (PET). This report presents the synthesis and
biological evaluation of (64)Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium (TPEP)
cations as novel PET radiotracers for
tumor imaging. Biodistribution studies were performed using the athymic nude mice bearing subcutaneous U87MG human
glioma xenografts to explore the impact of linkers, bifunctional
chelators (BFCs), and chelates on biodistribution characteristics of the (64)Cu-labeled TPEP
cations. Metabolism studies were carried out using normal athymic nude mice to determine the metabolic stability of four (64)Cu radiotracers. It was found that most (64)Cu radiotracers described in this study have significant advantages over (99m)Tc-Sestamibi for their high
tumor/heart and
tumor/muscle ratios. Both BFCs and linkers have significant impact on
biological properties of (64)Cu-labeled TPEP
cations. For example, (64)Cu(DO3A-xy-TPEP) has much lower liver uptake and better
tumor/liver ratios than (64)Cu(DO3A-xy-TPP), suggesting that TPEP is a better mitochondrion-targeting molecule than TPP. Replacing DO3A with DO2A results in (64)Cu(DO2A-xy-TPEP) (+), which has a lower
tumor uptake than (64)Cu(DO3A-xy-TPEP). Substitution of DO3A with
NOTA-Bn leads to a significant decrease in
tumor uptake for (64)Cu(NOTA-Bn-xy-TPEP). The use of
DOTA-Bn to replace DO3A has little impact on the
tumor uptake, but the
tumor/liver ratio of (64)Cu(DOTA-Bn-xy-TPEP) (-) is not as good as that of (64)Cu(DO3A-xy-TPEP), probably due to the aromatic
benzene ring in
DOTA-Bn. Addition of an extra acetamido group in (64)Cu(DOTA-xy-TPEP) results in a lower liver uptake, but
tumor/liver ratios of (64)Cu(DOTA-xy-TPEP) and (64)Cu(DO3A-xy-TPEP) are comparable due to a faster
tumor washout of (64)Cu(DOTA-xy-TPEP). Substitution of
xylene with the PEG 2 linker also leads to a significant reduction in both
tumor and liver uptake. MicroPET imaging studies on (64)Cu(DO3A-xy-TPEP) in athymic nude mice bearing U87MG
glioma xenografts showed that the
tumor was clearly visualized as early as 1 h postinjection with very high T/B contrast. There was very little metabolite (<2%) detectable in the urine and feces samples for (64)Cu(DO3A-xy-TPEP), (64)Cu(DOTA-Bn-xy-TPEP)(-), and (64)Cu(NOTA-Bn-xy-TPEP). Considering both
tumor uptake and T/B ratios (particularly
tumor/heart,
tumor/liver, and
tumor/muscle), it was concluded that (64)Cu(DO3A-xy-TPEP) is a promising PET radiotracer for imaging the MDR-negative
tumors.