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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

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Abstract

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.

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Acknowledgements

We wish to acknowledge Raffaella Rossin and Amy L. Vāvere for their help and discussions. We are very grateful for the technical assistance of Dawn Werner, Terry Sharp, Lori Strong, Nicole Fettig, Margaret Morris, Amanda Roth, Ann Stroncek and Jerrel Rutlin for animal handling and microPET imaging support, as well as Susan Adams for cell preparation. Thanks also to Tom Voller and the WUSTL cyclotron facility staff for radionuclide production. This work was partially supported by the National Institutes of Health/National Cancer Institute (NIH/NCI) (R24 CA86307). Small-animal PET imaging is supported by an NIH/NCI SAIRP grant (R24 CA86060) with additional support from the Small Animal Imaging Core (SAIC) of the Alvin J. Siteman Cancer Center at Washington University and Barnes-Jewish Hospital. The SAIC is supported by an NIH/NCI Support Grant P30 CA91842.

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Authors and Affiliations

  1. Dipartimento di Scienze Chimiche, Università di Camerino, via S. Agostino 1, 62032, Camerino, MC, Italy

    Simone Alidori, Giancarlo Gioia Lobbia, Grazia Papini, Maura Pellei & Carlo Santini

  2. I.C.I.S.-C.N.R., Corso Stati Uniti, 4, 35127, Padua, Italy

    Marina Porchia, Fiorenzo Refosco & Francesco Tisato

  3. Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, Campus Box 8225, St Louis, MO, 63110, USA

    Jason S. Lewis

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  1. Simone Alidori
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  2. Giancarlo Gioia Lobbia
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  3. Grazia Papini
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  4. Maura Pellei
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  5. Marina Porchia
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  7. Francesco Tisato
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  8. Jason S. Lewis
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  9. Carlo Santini
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Correspondence to Jason S. Lewis or Carlo Santini.

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Alidori, S., Gioia Lobbia, G., Papini, G. et al. 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. J Biol Inorg Chem 13, 307–315 (2008). https://doi.org/10.1007/s00775-007-0322-y

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  • DOI: https://doi.org/10.1007/s00775-007-0322-y

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