A (99m)Tc-labeled triphenylphosphonium derivative for the early detection of breast tumors

A greater mitochondrial membrane potential in tumor cells has been shown to enhance the accumulation of triphenyl phosphonium derivatives. The aim of this study was to synthesize and characterize (99m)Tc-labeled alkyl triphenyl phosphonium ((99m)Tc-Mito(10)-MAG3) for the early detection of breast tumors.

Mito(10)-MAG3 was synthesized by coupling (10-aminodecyl)triphenyl phosphonium bromide with NHS-MAG3 and radiolabeled with (99m)Tc. Biodistribution and pharmacokinetics of (99m)Tc-Mito(10)-MAG3 was investigated in female Sprague-Dawley rats. Initially, (99m)Tc-Mito(10)-MAG3 was tested in animals with established breast tumors. In a subsequent longitudinal study, the imaging efficacy of (99m)Tc(10)-Mito-MAG3 for detecting small, nonpalpable breast tumors was assessed after chemically inducting breast carcinoma. Tumors detected by imaging were allowed to grow to palpable size and confirmed by histology. The results were compared with (99m)Tc-MIBI.

The synthesis of Mito(10)-MAG3 was confirmed by mass spectrometry. The compound was radiolabeled with (99m)Tc to > 92% in a single step. The radiopharmaceutical exhibited fast blood clearance and low cardiac uptake. In the initial study, using animals with established breast tumors, (99m)Tc-Mito(10)-MAG3 imaging detected small lesions that were missed by palpation. In the longitudinal study, (99m)Tc-Mito(10)-MAG3 exhibited focal uptake in small breast tumors, which were confirmed by histology.

Imaging, using (99m)Tc-Mito(10)-MAG3, allowed the early detection of small neoplastic lesions in the mammary glands. The agent significantly reduced cardiac uptake, compared with (99m)Tc-MBIB. The phosphonium-based derivatives warrant further characterization and development as imaging agents for scintimammography.