Original Paper

JBIC Journal of Biological Inorganic Chemistry

, Volume 13, Issue 2, pp 307-315

First online:

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

  • Simone AlidoriAffiliated withDipartimento di Scienze Chimiche, Università di Camerino
  • , Giancarlo Gioia LobbiaAffiliated withDipartimento di Scienze Chimiche, Università di Camerino
  • , Grazia PapiniAffiliated withDipartimento di Scienze Chimiche, Università di Camerino
  • , Maura PelleiAffiliated withDipartimento di Scienze Chimiche, Università di Camerino
  • , Marina PorchiaAffiliated withI.C.I.S.-C.N.R.
  • , Fiorenzo RefoscoAffiliated withI.C.I.S.-C.N.R.
  • , Francesco TisatoAffiliated withI.C.I.S.-C.N.R.
  • , Jason S. LewisAffiliated withMallinckrodt Institute of Radiology, Washington University School of Medicine Email author 
  • , Carlo SantiniAffiliated withDipartimento di Scienze Chimiche, Università di Camerino Email author 

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Four novel 64Cu complexes ([64Cu(thp)4]+ (1), [64Cu(TPA)4]+ (2), [HC(CO2)(pzMe2)2 64Cu(thp)2] (3) and [HC(CO2)(tz)2 64Cu(thp)2] (4), [where thp is tris(hydroxymethyl)phosphine, TPA is 1,3,5-triaza-7-phosphaadamantane, pzMe2 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.


Positron emission tomography Copper-64 Radiopharmaceuticals Cancer