Rhenium and technetium tricarbonyl complexes anchored by pyrazole-based tripods: novel lead structures for the design of myocardial imaging agents

Abstract

This report describes the synthesis and biological evaluation of cationic (99m)Tc-tricarbonyl complexes anchored by ether-containing tris(pyrazolyl)methane or bis(pyrazolyl)ethanamine ligands to be applied in the design of radiopharmaceuticals for myocardial imaging: fac-[(99m)Tc(CO)(3){RC(pz)(3)}](+) (R = H (1a), MeOCH(2) (2a), EtOCH(2) (3a), (n)PrOCH(2) (4a)) and fac-[(99m)Tc(CO)(3){RNHCH(2)CH(pz)(2)}](+) (R = H (5a), MeO(CH(2))(2) (6a)) (pz = pyrazolyl). At the no carrier added level, complexes 1a-6a were obtained in high radiochemical yield (> 98%) by reaction of fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) with the corresponding tripod chelator in aqueous medium. All these complexes display a high in vitro and in vivo stability, except 6a which metabolizes in vivo yielding fac-[(99m)Tc(CO)(3){HO(CH(2))(2)NHCH(2)CH(pz)(2)}](+) (7a). Biological studies in mice have shown that among the radiotracers evaluated in this work, 3a, anchored by a tris(pyrazolyl)methane chelator bearing an ethyl methyl ether substituent, has the highest heart uptake (3.6 +/- 0.5%ID g(-1) at 60 min p.i.). Complex 3a presents also the best heart: blood, heart: liver and heart: lung ratios, appearing as the most promising as a potential myocardial imaging agent. The chemical identity of 1a-7a was ascertained by HPLC comparison with the previously reported fac-[Re(CO)(3){HC(pz)(3)}]Br (1) and with the novel fac-[Re(CO)(3){RC(pz)(3)}]Br (R = MeOCH(2) (2), EtOCH(2) (3), (n)PrOCH(2)(4)) and fac-[Re(CO)(3){RNHCH(2)CH(pz)(2)}]Br (R = H (5), MeO(CH(2))(2) (6) HO(CH(2))(2) (7)). The novel Re(I) tricarbonyl complexes, 2-7, were characterized by the common analytical techniques, including single crystal X-ray diffraction analysis. The solid state structure confirmed the presence of facial and tridentate (kappa(3)-N(3)) anchor ligands. Solution NMR studies have also shown that this kappa(3)-N(3) coordination mode is retained in solution for all complexes (2-7).

Synthesis, Characterization and Crystal Structure of Bis[1-methoxy-2,2,2-tris-(pyrazol-1-yl-κN2)ethane]-copper(II) Bis-perchlorate

“…1-Methoxy-2,2,2-tris(pyrazol-1-yl)ethane (1) ligand was synthesized according to the previously published procedure of Maria et al [17]. Copper(II)perchlorate hexahydrate was purchased from ACROS and used as received.…”

Ligand exchange and complex formation kinetics studied by NMR exemplified on fac-[(CO)3M(H2O)]+ (M=Mn, Tc, Re)

“…From this precursor a complex has to be formed which has no structural or metalbased reactivity. Since its first synthesis fac-[(CO) 3 Tc(H 2 O)] + [28] became one of these precursors and a large number of substitution products have now been synthesized and structurally characterized [20,[29][30][31][32][33][34]. Understanding reactivity and mechanisms of substitution of the three labile water molecules became an important issue especially in the context of synthesis of similar technetium and rhenium complexes.…”

Two New Imidazole‐Based Heteroscorpionate Ligands

“…[ It is noteworthy, that Santos and co-workers [13] reported in 2007 on the synthesis of some rhenium(I) and technetium(I) complexes bearing bis-and tris(pyrazol-1-yl)ethanol ethers. The technetium complexes showed to be potent radiotracers for myocardial perfusion imaging.…”

“…[14] Complex 9 precipitates from the reaction mixture, crystallizing with 1 equiv. of THF and was spectroscopically characterised by 1 H, 13 C{ 1 H} and 31 P NMR as well as elemental analysis and IR spectroscopy. As expected, the ruthenium(II) complex exhibits sharp signals in the NMR spectra.…”