Synthesis, in vitro and in vivo characterization of (64)Cu(I) complexes derived from hydrophilic tris(hydroxymethyl)phosphane and 1,3,5-triaza-7-phosphaadamantane ligands

• Published in: Journal of biological inorganic chemistry Vol. 13; no. 2; p. 307
• Main Authors: Alidori, Simone, Gioia Lobbia, Giancarlo, Papini, Grazia, Pellei, Maura, Porchia, Marina, Refosco, Fiorenzo, Tisato, Francesco, Lewis, Jason S, Santini, Carlo
• Format: Journal Article
• Language: English
• Published: Germany 01.02.2008
• Subjects: Adamantane - analogs & derivatives; Adamantane - blood; Adamantane - chemical synthesis; Adamantane - pharmacokinetics; Animals; Cell Line, Tumor; Copper Radioisotopes - chemistry; Copper Radioisotopes - pharmacokinetics; Copper Radioisotopes - therapeutic use; Female; Ligands; Mice; Mice, Inbred BALB C; Organophosphorus Compounds - blood; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - pharmacokinetics; Phosphines - blood; Phosphines - chemical synthesis; Phosphines - pharmacokinetics; Positron-Emission Tomography; Radiopharmaceuticals - blood; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Rats
• ISSN: 0949-8257
• DOI: 10.1007/s00775-007-0322-y

Four novel (64)Cu complexes ([(64)Cu(thp)(4)](+) (1), [(64)Cu(TPA)(4)](+) (2), [HC(CO(2))(pz(Me2))(2) (64)Cu(thp)(2)] (3) and [HC(CO(2))(tz)(2) (64)Cu(thp)(2)] (4), [where thp is tris(hydroxymethyl)phosphine, TPA is 1,3,5-triaza-7-phosphaadamantane, pz(Me2) is 3,5-dimethylpyrazole and tz is 1,2,4-triazole] were successfully synthesized and characterized. The complexes were produced in high radiochemical purity and yield (more than 98%) without the need for further purification. Their logP values and serum stabilities were measured and in vitro behavior was observed in cultured EMT-6 cells. The logP values (+/- standard deviation) obtained were -2.26 +/- 0.04 (1), 0.01 +/- 0.01 (2), -1.24 +/- 0.03 (3) and -2.06 +/- 0.03 (4). Complex 3 demonstrated the highest serum stability, with approximately 33% of the complex still intact after 1-h incubation. Complex 2 showed a rapid cell-association with EMT-6 cells, with more than 8.5% association at 2 h. This association was significantly higher (P < 0.001) than for the other three compounds after a 2-h incubation (1, 1.21%; 3, 0.63%; 4, 2.75%). Biodistribution and small-animal positron emission tomography/computed tomography was undertaken with 1 in mice bearing EMT-6 tumors. EMT-6 tumor uptake was high at 1 h (7.71 +/- 2.17 %ID/g) and decreased slowly over 24 h (4 h, 4.90 +/- 0.78 %ID/g; 24 h, 3.74 +/- 0.73 %ID/g). The PET/CT images show that the EMT-6 tumors can be visualized at all time points. In this proof-of-concept study, we have successfully synthesized and characterized a novel series of versatile water-soluble Cu(I) complexes containing monophosphine ligands. We also report the use of 1 as a building block for new radiopharmaceuticals, perhaps the first time such a method has been used in the production of copper radiopharmaceuticals.