title: 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).
authors.affiliation: Departamento de Química, ITN, Estrada Nacional 10, 2686-953, Sacavém, Codex, Portugal.
authors.forename: Leonor
authors.initials: L
authors.lastname: Maria
authors.forename: Susana
authors.initials: S
authors.lastname: Cunha
authors.forename: Margarida
authors.initials: M
authors.lastname: Videira
authors.forename: Lurdes
authors.initials: L
authors.lastname: Gano
authors.forename: António
authors.initials: A
authors.lastname: Paulo
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Santos
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
mesh_terms: D000818:Animals; D002244:Carbon / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003952:Diagnostic Imaging / Q000379:methods*; D006321:Heart / Q000187:drug effects*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012211:Rhenium / Q000737:chemistry*; D013667:Technetium / Q000737:chemistry*
chemical_list: D008024:Ligands; D011720:Pyrazoles; C031280:pyrazole; D012211:Rhenium; D013667:Technetium; D002244:Carbon