JBIC Journal of Biological Inorganic Chemistry

, Volume 9, Issue 7, pp 859–872 | Cite as

153Sm and 166Ho complexes with tetraaza macrocycles containing pyridine and methylcarboxylate or methylphosphonate pendant arms

  • Fernanda Marques
  • Krassimira P. Guerra
  • Lurdes Gano
  • Judite Costa
  • M. Paula Campello
  • Luís M. P. Lima
  • Rita Delgado
  • Isabel Santos
Original Article


A set of tetraaza macrocycles containing pyridine and methylcarboxylate (ac3py14) or methylphosphonate (MeP2py14 and P3py14) pendant arms were prepared and their stability constants with La3+, Sm3+, Gd3+ and Ho3+ determined by potentiometry at 25 °C and 0.10 M ionic strength in NMe4NO3. The metal:ligand ratio for 153Sm and 166Ho and for ac3py14, MeP2py14 and P3py14, as well as the pH of the reaction mixtures, were optimized to achieve a chelation efficiency higher than 98%. These radiocomplexes are hydrophilic and have a significant plasmatic protein binding. In vitro stability was studied in physiological solutions and in human serum. All complexes are stable in saline and PBS, but 20% of radiochemical impurities were detected after 24 h of incubation in serum. Biodistribution studies in mice indicated a slow rate of clearance from blood and muscle, a high and rapid liver uptake and a very slow rate of total radioactivity excretion. Some bone uptake was observed for complexes with MeP2py14 and P3py14, which was enhanced with time and the number of methylphosphonate groups. This biological profile supports the in vitro instability found in serum and is consistent with the thermodynamic stability constants found for these complexes.


Lanthanides Pendant arms Radiopharmaceuticals Stability constants Tetraaza macrocycles 



The authors acknowledge the financial support from Fundação para a Ciência e a Tecnologia (FCT) and POCTI, with co-participation of the European Community fund FEDER (project nos. POCTI/2000/ESP/35877 and POCTI/2000/CBO/35859). This work was also partially supported by COST ACTION D18. K.P.G. also acknowledges Fundação para a Ciência e Tecnologia (FCT) for a grant (SFRH/BD/6492/2001). The authors thank the ITN Research Portuguese Reactor Group for the production of 153Sm and 166Ho.


  1. 1.
    Hoefnagel CA (1991) Eur J Nucl Med 18:408–431PubMedGoogle Scholar
  2. 2.
    Hoefnagel CA (1998) Ann Nucl Med 12:61–70PubMedGoogle Scholar
  3. 3.
    Volkert WA, Goeckeler WF, Ehrhardt GJ, Ketring AR (1991) J Nucl Med 32:174–185PubMedGoogle Scholar
  4. 4.
    Wessels BW, Mears CF (2000) Semin Radiat Oncol 10:115–122PubMedGoogle Scholar
  5. 5.
    Volkert WA, Hoffman TJ (1999) Chem Rev 9:2269–2292CrossRefGoogle Scholar
  6. 6.
    Ercan MT, Caglar M (2000) Curr Pharm Des 6:1085–1121PubMedGoogle Scholar
  7. 7.
    Vallabhajosula S (2001) In: Khalkhali I, Maublant J, Goldsmith SJ (eds) Nuclear oncology: diagnosis and therapy. Lippincott Williams & Wilkins, Philadelphia, pp xxx–yyyGoogle Scholar
  8. 8.
    Delaloye AB, Delaloye B (1995) Eur J Nucl Med 22:571–580PubMedGoogle Scholar
  9. 9.
    Kairemo KJ (1996) Acta Oncol 35:343–355PubMedGoogle Scholar
  10. 10.
    von Mehren M, Adams GP, Weiner LM (2003) Annu Rev Med 54:343–369CrossRefPubMedGoogle Scholar
  11. 11.
    Waldmann TA (2003) Nat Med 9:269–277CrossRefPubMedGoogle Scholar
  12. 12.
    Behr TM, Gotthardt M, Barth A, Béhé M (2001) Q J Nucl Med 45:189–200PubMedGoogle Scholar
  13. 13.
    Froidevaux S, Eberle AN (2002) Biopolymers 66:161–183CrossRefPubMedGoogle Scholar
  14. 14.
    Jong M, Kwekkeboom D, Valkema R, Krenning EP (2003) Eur J Nucl Med 30:463–469Google Scholar
  15. 15.
    Reubi JC (2003) Endocrinol Rev 24:389–427CrossRefGoogle Scholar
  16. 16.
    Deshpande SV, DeNardo SJ, Kukis DL, Moi MK, McCall MJ, DeNardo GL, Meares CF (1990) J Nucl Med 31:473–479PubMedGoogle Scholar
  17. 17.
    Li M, Meares CF, Zhong GR, Miers L, Xiong CY, DeNardo SJ (1994) Bioconj Chem 5:101–104Google Scholar
  18. 18.
    Meredith RF, Partridge EE, Alvarez RD, Khazaeli MB, Plott G, Russell CD, Wheeler RH, Liu T, Grizzle WE, Schlom J, LoBuglio AF (1996) J Nucl Med 37:1491–1496PubMedGoogle Scholar
  19. 19.
    Otte A, Herrmann R, Heppeller A, Behe M, Jermann E, Powell P, Maecke HR, Muller J (1999) Eur J Nucl Med 26:1439–1447CrossRefPubMedGoogle Scholar
  20. 20.
    Breeman WA, de Jong M, Visser TJ, Erion JL, Krenning EP (2003) Eur J Nucl Med Mol Imaging 30:917–920PubMedGoogle Scholar
  21. 21.
    Neves M, Reis MF, Waerenborgh F, Martinho E, Patrício L (1987) Inorg Chim Acta 140:359–360CrossRefGoogle Scholar
  22. 22.
    Neves M, Kling A, Lambrecht RM (2002) Appl Radiat Isot 57:657–664CrossRefPubMedGoogle Scholar
  23. 23.
    Bayouth JE, Macey DJ, Kasi LP, Garlich JR, McMillan K, Dimopoulos MA, Champlin RE (1995) J Nucl Med 36:730–737PubMedGoogle Scholar
  24. 24.
    Dadachova E, Mirzadeh S, Smith SV, Knapp FF Jr, Hetherington EL (1997) Appl Radiat Isot 48:477–481CrossRefPubMedGoogle Scholar
  25. 25.
    Fani M, Vranjes S, Archimandritis SC, Potamianos S, Xanthopoulos S, Bouziotis P, Varvarigou AD (2002) Appl Radiat Isot 57:665–674CrossRefPubMedGoogle Scholar
  26. 26.
    Ando A, Ando I, Tonami N, Kinuya S, Kazuma K, Kataiwa A, Nakagawa M, Fujita N (1998) Nucl Med Commun 19:587–591PubMedGoogle Scholar
  27. 27.
    Brenner W, Kampen WU, Kampen AM, Henze E (2001) J Nucl Med 42:230–236PubMedGoogle Scholar
  28. 28.
    Liu S, Edwards DS (2001) Bioconj Chem 12:7–34CrossRefGoogle Scholar
  29. 29.
    Thöm VJ, Fox CC, Boeyens JCA, Hancock RD (1984) J Am Chem Soc 106:5947–5955Google Scholar
  30. 30.
    Chang CA, Liu YL, Chen CY, Chou XM (2001) Inorg Chem 40:3448–3455CrossRefPubMedGoogle Scholar
  31. 31.
    Izatt RM, Pawlak K, Bradshaw JS, Bruening RL (1995) Chem Rev 95:2529–2586Google Scholar
  32. 32.
    Anderegg G, Arnaud-Neu F, Delgado R, Felcman J, Popov K (2004) Journal (in press)Google Scholar
  33. 33.
    Alves FC, Donato P, Sherry AD, Zaheer A, Zhang S, Lubag AJM, Merritt ME, Lenkinski RE, Frangioni JV, Neves M, Prata MIM, Santos AC, de Lima JJP, Geraldes CFGC (2003) Invest Radiol 38:750–760CrossRefPubMedGoogle Scholar
  34. 34.
    Banerjee S, Samuel G, Kothari K, Unni PR, Sarma HD, Pillai MRA (2001) Nucl Med Biol 28:205–213CrossRefPubMedGoogle Scholar
  35. 35.
    Kim WD, Hrncir DC, Kiefer GE, Sherry AD (1995) Inorg Chem 34:2225–2232Google Scholar
  36. 36.
    Kim WD, Kiefer GE, Maton F, McMillan K, Muller RN, Sherry AD (1995) Inorg Chem 34:2233–2243Google Scholar
  37. 37.
    Aime S, Botta M, Crich SG, Giovenzana GB, Jommi G, Pagliarin R, Sisti M (1997) Inorg Chem 36:2992–3000CrossRefPubMedGoogle Scholar
  38. 38.
    Aime S, Botta M, Frullano L, Crich SG, Giovenzana G, Pagliarin R, Palmisano G, Sirtori FR, Sisti M (2000) J Med Chem 43:4017–4024CrossRefPubMedGoogle Scholar
  39. 39.
    Aime S, Gianolio E, Corpillo D, Cavallotti C, Palmisano G, Sisti M, Giovenzana GB, Pagliarin R (2003) Helv Chim Acta 86:615–632CrossRefGoogle Scholar
  40. 40.
    Costa J, Delgado R (1993) Inorg Chem 32:5257–5265Google Scholar
  41. 41.
    Costa J, Delgado R, Drew MGB, Félix V (1998) J Chem Soc Dalton Trans 1063–1071Google Scholar
  42. 42.
    Guerra KP, Delgado R, Lima LMP, Drew MGB, Félix V (2004) Dalton Trans (in press)Google Scholar
  43. 43.
    Schwarzenbach G, Flaschka W (1969) Complexometric titrations. Methuen, LondonGoogle Scholar
  44. 44.
    Schwarzenbach G, Biedermann W (1948) Helv Chim Acta 31:331–340Google Scholar
  45. 45.
    Gran G (1952) Analyst (London) 77:661–671Google Scholar
  46. 46.
    Rossotti FJ, Rossotti HJ (1965) J Chem Educ 42:375–378Google Scholar
  47. 47.
    Gans P, Sabatini A, Vacca A (1996) Talanta 43:1739–1753CrossRefGoogle Scholar
  48. 48.
    Geraldes CFGC, Sherry AD, Cacheris WP (1989) Inorg Chem 28:3336–3341Google Scholar
  49. 49.
    Popov K, Niskanen E, Rönkkömäki H, Lajunen LHJ (1999) New J Chem 23:1209–1213CrossRefGoogle Scholar
  50. 50.
    Alderighi L, Gans P, Ienco A, Peters D, Sabatini A, Vacca A (1999) Coord Chem Rev 184:311–318CrossRefGoogle Scholar
  51. 51.
    Madsen SL, Bannochie CJ, Martell AE, Mathias CJ, Welch MJ (1990) J Nucl Med 31:1662–1668PubMedGoogle Scholar
  52. 52.
    Lukeš I, Kotek J, Vojtíšek P, Hermann P (2001) Coord Chem Rev 216–217:287–312Google Scholar
  53. 53.
    Kotek J, Hermann P, Císařová I, Rohovec J, Lukeš I (2001) Inorg Chim Acta 317:324–330CrossRefGoogle Scholar
  54. 54.
    Popov K, Rönkkömäki H, Lajunen LHJ (2001) Pure Appl Chem 73:1641–1677Google Scholar
  55. 55.
    Neumaier B, Rösch F (1999) Radiochim Acta 84:201–204Google Scholar
  56. 56.
    Li WP, Smith CJ, Cutler CS, Hoffman TJ, Ketring AR, Jurisson SS (2003) Nucl Med Biol 30:241–251CrossRefPubMedGoogle Scholar
  57. 57.
    Harris WR, Chen Y (1992) Inorg Chem 31:5001–5006Google Scholar
  58. 58.
    Chen Y, Harris WR (1999) Acta Chim Sinica 57:503–509Google Scholar

Copyright information

© SBIC 2004

Authors and Affiliations

  • Fernanda Marques
    • 1
  • Krassimira P. Guerra
    • 2
  • Lurdes Gano
    • 1
  • Judite Costa
    • 2
    • 3
  • M. Paula Campello
    • 1
  • Luís M. P. Lima
    • 2
  • Rita Delgado
    • 2
    • 4
  • Isabel Santos
    • 1
  1. 1.Instituto Tecnológico e NuclearSacavémPortugal
  2. 2.Instituto de Tecnologia Química e BiológicaUNLOeirasPortugal
  3. 3.Faculdade de FarmáciaUniversidade de LisboaLisbonPortugal
  4. 4.Instituto Superior TécnicoLisbonPortugal

Personalised recommendations