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.
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.
Dipartimento di Scienze Chimiche, Università di Camerino, via S. Agostino 1, 62032, Camerino, MC, Italy.
Simone
S
Alidori
Giancarlo
G
Gioia Lobbia
Grazia
G
Papini
Maura
M
Pellei
Marina
M
Porchia
Fiorenzo
F
Refosco
Francesco
F
Tisato
Jason S
JS
Lewis
Carlo
C
Santini
D000218:Adamantane / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D009943:Organophosphorus Compounds / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010720:Phosphines / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats
C501763:1,3,5-triaza-7-phosphaadamantane; D003301:Copper Radioisotopes; D008024:Ligands; D009943:Organophosphorus Compounds; D010720:Phosphines; D019275:Radiopharmaceuticals; D000218:Adamantane; C505069:tris(hydroxymethyl)phosphine