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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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
References
Love C, Din AS, Tomas MB, Kalapparambath TP, Palestro CJ (2003) Radiographics 23:341–358
Coleman RE (2001) Cancer Treat Rev 27:165–176
Pinski J, Dorff TB (2005) Eur J Cancer 41:932–940
Serafini AN (2001) J Nucl Med 42:895–906
Bagi CM (2005) Adv Drug Deliv Rev 57:995–1010
Reisfield GM, Silberstein EB, Wilson GR (2005) Am J Hos Palliat Med 22:41–46
Ogawa K, Mukai T, Asano D, Kawashima H, Kinuya S, Shiba K, Hashimoto K, Mori H, Saji H (2007) J Nucl Med 48:122–127
Uehara T, Jin ZL, Ogawa K, Akizawa H, Hashimoto K, Nakayama M, Arano Y (2007) Nucl Med Biol 34:79–87
Ogawa K, Mukai T, Arano Y, Otaka A, Ueda M, Uehara T, Magata Y, Hashimoto K, Saji H (2006) Nucl Med Biol 33:513–520
Ogawa K, Mukai T, Arano Y, Ono M, Hanaoka H, Ishino S, Hashimoto K, Nishimura H, Saji H (2005) Bioconjugate Chem 16:751–757
Ogawa K, Mukai T, Arano Y, Hanaoka H, Hashimoto K, Nishimura H, Saji H (2004) J Labelled Compd Radiopharm 47:753–761
Zhang S, Gangal G, Uluda H (2007) Chem Soc Rev (in press). doi:10.1039/b512310k
Verbeke K, Rozenski J, Cleynhens B, Vanbilloen H, Groot T, Weyns N, Bormans G, Verbruggen A (2002) Bioconjugate Chem 13:16–22
Shigematsu M, Shiomi S, Iwao H, Ochi H (2002) Ann Nucl Med 16:55–59
Doubsky J, Laznicek M, Laznickova A, Leseticky L (2004) J Radioanal Nucl Chem 260:53–59
El-Mabhouh A, Angelov CA, Cavell R, Mercer JR (2006) Nucl Med Biol 33:715–722
Santos I, Paulo A, Correia JDG (2005) Top Curr Chem 252:45–84
Alberto R (2005) Top Curr Chem 252:1–44
Schibli R, Schubiger AP (2002) Eur J Nucl Med 29:1529–1542
Garcia R, Gano L, Maria L, Paulo A, Santos I, Spies H (2006) J Biol Inorg Chem 11:769–782
Alves S, Paulo A, Correia JDG, Domingos Â, Santos I (2002) J Chem Soc Dalton Trans 4714–4719
Vitor RF, Alves S, Correia JDG, Paulo A, Santos I (2004) J Organomet Chem 689:4764–4774
Alves S, Paulo A, Correia JDG, Gano L, Smith CJ, Santos I (2005) Bioconjugate Chem 16:438–449
Alves S, Correia JDG, Santos I, Veerendra B, Sieckman GL, Hoffman, Rold T, Retzloff L, McCrate J, Prasanphanich A, Smith CJ (2006) Nucl Med Biol 33:625–634
Worms KH, Shmidt-Dunker M (1972) In: Kosolapoff GM, Maier L (eds) Organic phosphorus compounds, vol 7. Wiley, New York, chap 18
Kantoci D, Denike JK, Wechter WJ (1996) Synth Commun 26:2037–2043
Kubicek V, Rudovsky J, Kotek J, Hermann P, Vander LE, Muller RN, Kolar ZI, Wolterbeek HTh, Peters JA, Lukes I (2005) J Am Chem Soc 127:16477–16485
Alberto R, Schibli R, Egli A, Schubiger PA., Herrmann WA, Artus G, Abram U, Kaden TA (1995) J Organomet Chem 493:119–127
Lazarova N, James S, Babich J, Zubieta J (2004) Inorg Chem Commun 7:1023–1026
Farrugia LJ (1999) J Appl Crystallogr 32:837–838
Altomare A, Burla MC, Camalli M, Cascarano G, Giacovazzo G, Guagliardi A, Moliterini AGG, Polidoro G, Spagna R (1999) J Appl Crystallogr 32:115–119
Sheldrick GM,(1997) SHELXL-97. Program for the solution of crystal structure. University of Gottingen, Germany
Farrugia LJ (1997) J Appl Crystallogr 30:565
Alberto R (2004) In: McLeverty JA, Meyer TJ (eds) Comprehensive coordination chemistry II, vol 5. Elsevier–Pergamon, Amsterdam, pp 127–270
Mundwiler S, Waibel R, Spingler B, Kunze S, Alberto R (2005) Nucl Med Biol 32:473–484
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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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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DOI: https://doi.org/10.1007/s00775-007-0215-0