Metal complexes with potential use in estrogen receptor imaging

  1. Saray Argibay Otero
Dirigée par:
  1. Ezequiel M. Vázquez López Directeur/trice
  2. Rosa Carballo Rial Directeur/trice

Université de défendre: Universidade de Vigo

Année de défendre: 2021

  1. Jorge Bravo Bernárdez President
  2. Ana Belén Lago Blanco Secrétaire
  3. Vanesa Fernández Moreira Rapporteur

Type: Thèses


The 99mTc compounds with selective affinity for estrogen receptor (ER) can be used in tumour and hormone-dependent diseases diagnosis (for example breast cancer). The early diagnosis of this disease is important to avoid unnecessary biopsies, with the expense of resources and patient suffering that this entails. Due to the difficulty of working with radioactive materials such as technetium and trying to save time and costs, in the early phases of the design of these radiopharmaceuticals the rhenium complexes are usually used as surrogates due to the high chemical similarity between them. For these reasons, we have focused primarily on the design and synthesis of rhenium(I) coordination compounds and then we have realized the study of the behaviour of some of these ligands against the [99mTc(CO)3(H2O)3]+ precursor to verify their similar reactivity, besides their stability in a biological medium. Our radiopharmaceutical model design is based on the integrated approach, in which we try to obtain complexes with potential affinity for the target receptor inspired by the interactions that residues of the estrogen receptor binding site establish with certain molecules (such as 17 -estradiol agonist or raloxifene antagonist) and which are responsible for high affinity. Only when the suitably chosen ligands are bound to the metal, are they available in a suitable form to interact with ER, which has advantages from the point of view of radiopharmacy. In the present work we describe the design and the synthesis of several hydrazone and thiosemicarbazone ligands. These compounds can acting as bidentate (hydrazones HL11-16 and the thiosemicarbazones HL21-27) and as tridentate (thiosemicarbazones H2L32-36 and HL41-49). Besides, different coordination modes were observed for one same ligand and even dinuclear structures in many cases. All the compounds were characterized by elemental analysis, mass spectroscopy, spectroscopic methods such as NMR and IR and the crystal structure analysis for a large number of these compounds was performed. In some cases, we observed that the halide complexes of thiosemicarbazones HL25-27 are unstable in solution, forming interesting dinuclear species which present different coordination modes, orientation of the ligands and even different bridge atoms between metal centres. Anionic complexes, of general formula [Re(Ln)(CO)3]–, could also be obtained from double deprotonation of the thiosemicarbazones H2L32-36 ligands, where the ligand is a S,N,O tridentate. The other tridentate ligands are HL41-49, where a pyridine group is added to the thiosemicarbazone chain. We could also observed how the attack of an alcohol group to the C2 carbon in these ligands yields cationic or neutral complexes (depending on the reaction medium). The studies with the 99mTc precursor were centered on the reactivity against to thiosemicarbazone ligands HL21-24 and H2L32-36. The HPLC-radiochomatograms of the reaction media show signals at the same retention time than rhenium complexes. Besides, the stability of the Tc(32-36) complexes was confirmed by HPLC analysis of blood and urine samples from mice injected with these compounds. Finally, studies of affinity for ER and ER on most of the ligands and their complexes obtained have been realized. As expected, neither ligand shows affinity for this receptor. The calculated Ki helps us to compare the complexes in order to try to improve the affinity for ER in new future designs.