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A new bisphosphonate-containing 99mTc(I) tricarbonyl complex potentially useful as bone-seeking agent: synthesis and biological evaluation

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Abstract

Aiming to develop new bone-seeking radiotracers based on the organometallic core fac-[99mTc(CO)3]+ with improved radiochemical and biological properties, we have prepared new conjugates with phosphonate pendant groups. The conjugates comprise a chelating unit for metal coordination, which corresponds to a pyrazolyl-containing backbone (pz) with a N,N,N donor-atom set, and a pendant diethyl phosphonate (pz-MPOEt), phosphonic acid (pz-MPOH) or a bisphosphonic acid (pz-BPOH) group for bone targeting. Reactions of the conjugates with the precursor [99mTc(H2O)3(CO)3]+ yielded (mote than 95%) the single and well-defined radioactive species [99mTc(CO)3(κ3-pz-MPOEt)]+ (1a), [99mTc(CO)3(κ3-pz-MPOH]+ (2a) and [99mTc(CO)3(κ3-pz-BPOH)]+ (3a), which were characterized by reversed-phase high-performance liquid chromatography . The corresponding Re surrogates (1–3), characterized by the usual analytical techniques, including X-ray diffraction analysis in the case of 1, allowed for macroscopic identification of the radioactive conjugates. These radioactive complexes revealed high stability both in vitro (phosphate-buffered saline solution and human plasma) and in vivo, without any measurable decomposition. Biodistribution studies of the complexes in mice indicated a fast rate of blood clearance and high rate of total radioactivity excretion, occurring primarily through the renal–urinary pathway in the case of complex 3a. Despite presenting moderate bone uptake (3.04 ± 0.47% injected dose per gram of organ, 4 h after injection), the high stability presented by 3a and its adequate in vivo pharmacokinetics encourages the search for new ligands with the same chelating unit and different bisphosphonic acid pendant arms.

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Scheme 1
Scheme 2
Fig. 1
Scheme 3
Scheme 4
Fig. 2

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Abbreviations

Boc:

tert-Butoxycarbonyl

BP:

Bisphosphonate

COSY:

Correlation spectroscopy

DCC:

N,N′-Dicyclohexylcarbodiimide

HMDP:

Hydroxymethylenediphosphonate

HOBt:

1-Hydroxybenzotriazole

HPLC:

High-performance liquid chromatography

HSQC:

Heteronuclear single quantum coherence

ID:

Injected dose

MDP:

Methylenediphosphonate

MP:

Monophosphonate

pz:

Pyrazolyl-containing backbone

RP:

Reversed phase

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Acknowledgements

This work was partially supported by the Fundação para a Ciência e Tecnologia (FCT) through the project POCI/SAU-FCF/58855/2004, and by COST ACTION B12. We thank Mallinkrodt-Tyco for financial support. B.L.O. and E.P. would like to thank the FCT for BI grants. We wish to acknowledge the Mass Spectrometry Laboratory for performing the electrospray ionization mass spectrometry determination at the Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.

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Authors and Affiliations

  1. Departamento de Química, ITN, Estrada Nacional 10, 2686-953, Sacavém Codex, Portugal

    Elisa Palma, Bruno L. Oliveira, João D. G. Correia, Lurdes Gano, Leonor Maria, Isabel C. Santos & Isabel Santos

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  1. Elisa Palma
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  2. Bruno L. Oliveira
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  3. João D. G. Correia
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  4. Lurdes Gano
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  5. Leonor Maria
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  6. Isabel C. Santos
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  7. Isabel Santos
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Correspondence to Isabel Santos.

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Palma, E., Oliveira, B.L., Correia, J.D.G. et al. A new bisphosphonate-containing 99mTc(I) tricarbonyl complex potentially useful as bone-seeking agent: synthesis and biological evaluation. J Biol Inorg Chem 12, 667–679 (2007). https://doi.org/10.1007/s00775-007-0215-0

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