⁶⁴Cu-Labeled Triphenylphosphonium and Triphenylarsonium Cations as Highly Tumor-Selective Imaging Agents

Abstract

This report presents synthesis and evaluation of the 64Cu-labeled triphenylphosphonium (TPP) cations as new radiotracers for imaging tumors by positron emission tomography. Biodistribution properties of 64Cu-L1, 64Cu-L2, 64Cu-L3, and 99mTc-Sestamibi were evaluated in athymic nude mice bearing U87MG human glioma xenografts. The most striking difference is that 64Cu-L1, 64Cu-L2, and 64Cu-L3 have much lower heart uptake (<0.6% ID/g) than 99mTc-Sestamibi ( approximately 18% ID/g) at >30 min p.i. Their tumor/heart ratios increase steadily from approximately 1 at 5 min p.i. to approximately 5 at 120 min p.i. The tumor/heart ratio of 64Cu-L3 is approximately 40 times better than that of 99mTc-Sestamibi at 120 min postinjection. Results from in vitro assays show that 64Cu-L1 is able to localize in tumor mitochondria. The tumor is clearly visualized in the tumor-bearing mice administered with 64Cu-L1 as 30 min postinjection. The 64Cu-labeled TPP/TPA cations are very selective radiotracers that are able to provide the information of mitochondrial bioenergetic function in tumors by monitoring mitochondrial potential in a noninvasive fashion.

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…691–694,730 Using bifunctional chelators, several TPP + -based mitochondria-targeted 64 Cu complexes were synthesized and tested in vivo. 691–694 The effects of the linker, targeting moiety, bifunctional chelator, and molecular charge were studied in order to select the best candidates for tumor imaging. In that series of publications, various mitochondria-targeted TPP + or TPEP-based 64 Cu complexes (Chart 90) were evaluated in vivo for tumor imaging and monitoring of the multidrug resistance transport function in tumors of different origin.…”

“…Of all of the analogs tested, based on high tumor uptake and high T/B ratios 64 Cu(DO3A-xy)TPEP (Chart 90), was selected as the most promising candidate for tumor imaging. 88,691,693,694,730–732 64 Cu(DO3A-xy)TPEP was found to have a better tumor selectivity than 99m Tc-MIBI (Chart 91). …”

64Cu-Labeled 2-(Diphenylphosphoryl)ethyldiphenylphosphonium Cations as Highly Selective Tumor Imaging Agents: Effects of Linkers and Chelates on Radiotracer Biodistribution Characteristics

“…MicroPET imaging data show that the tumor could be visualized as early as 30 min p.i. in the tumor-bearing mice administered with 64 Cu(DO3A-xy-TPP) (14). However, its high liver uptake remains a significant challenge for 64 Cu(DO3A-xy-TPP) to be clinically useful as a PET radiotracer.…”

Triphenylphosphonium Cations of the Diterpenoid Isosteviol: Synthesis and Antimitotic Activity in a Sea Urchin Embryo Model

“…35 In addition, 64 Cu-labeled triphenylphosphonium cations containing 1,4,7,10-tetraazacyclododecane moieties were used successfully as novel radiotracers for imaging tumors by positron-emission tomography. 36,37 It is worth noting that among natural products only 20,29-dihydrobetulinic acid and 3-epi-20,29-dihydrobetulinic acid have been conjugated with the TPP cation through a trimethylene linker, yielding derivatives with a markedly increased cytotoxicity against human cancer cells. 13c A lipophilic polymethylene linker is the only one reported to connect the TPP cation to a small molecule, 13c,30−40 whereas for a water-soluble isosteviol triethylammonium salt, a hydrophilic poly(ethylene glycol) (PEG) linker binds together the diterpenoid skeleton and the N + Et 3 moiety.…”