Influence of the ligand donor atoms on the in vitro stability of rhenium(I) and technetium (I)-99m complexes with pyrazole-containing chelators: Experimental and DFT studies

The new pyrazole-containing ligand 3,5-Me2pz(CH2)2S(CH2)2COOH (L1H) was synthesized and used to prepare the complexes fac-[M(κ3-L1)(CO)3] (M = Re (1), 99mTc(1a)), which were obtained in high yield albeit with a low specific activity in the case of 99mTc. The X-ray diffraction analysis of 1 confirmed that L1 coordinates to the metal as monoanionic and through a (N,S,O) donor atom set. Challenge experiments of 1a against cysteine and histidine showed that this complex suffers considerable transchelation in vitro. This contrasts with the behavior exhibited by the related complex fac-[99mTc(κ3-L2)(CO)3] (2a) (L2 = 3,5-Me2pz-(CH2)2NH-CH2-COO), anchored by a (N2O)-tridentate ligand. Biodistribution studies of 1a and 2a in mice indicated that both compounds have a relatively similar biological profile. Nevertheless, the fastest blood clearance and minor hepatic retention found for 2a has shown that this complex is more adequate to be further explored in radiopharmaceutical sciences. DFT calculations (ADF program) were performed for these neutral complexes and related cationic M(I) (M = Re, Tc) tricarbonyl complexes anchored by pyrazole-containing ligands, in order to have a better understanding of the influence of the donor atom set (N,N,O vs. N,O,S; N,N,N vs. N,N,S vs. N,S,S) on their in vitro stability. The differences of the calculated binding energies are not significant, suggesting that the in vitro behavior of these Re(I)/Tc(I) tricarbonyl complexes is not determined by thermodynamic factors.

The pyrazolyl-containing ligands 3,5-Me2pz(CH2)2S(CH2)2COOH (L1H) and 3,5-Me2pz(CH2)2O(CH2)2COOH (L2H) form well defined tricarbonyl complexes of the type fac-[M(κ3-L)(CO)3] (L = L1, M = Re (1), 99mTc (1a); L = L2, M = Re (2), 99mTc (2a)). In these complexes the chelators act as monoanionic and tridentate through N,S,O (1/1a) and N2O (2/2a) donor atom sets. Both compounds present a relatively similar biological profile in mice, but the introduction of the thioether group in 1a enhanced its in vitro reactivity towards cysteine and histidine. DFT calculations performed for the neutral 1/1a and 2/2a, as well as for other related cationic complexes anchored by neutral ligands, have shown that the anionic ligands are softer than the neutral ones and make stronger bonds with the M(CO)3 fragements. For both families the replacement of nitrogen by a sulfur donor atom leads to slightly less stable complexes (ΔE ∼ 4–10 kcol/mol).Figure optionsDownload as PowerPoint slide