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

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Abstract
This report describes the synthesis and biological evaluation of cationic 99mTc–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-[99mTc(CO)3{RC(pz)3}]+ (R = H (1a), MeOCH2 (2a), EtOCH2 (3a), nPrOCH2 (4a)) and fac-[99mTc(CO)3{RNHCH2CH(pz)2}]+ (R = H (5a), MeO(CH2)2 (6a)) (pz = pyrazolyl). At the no carrier added level, complexes 1a–6a were obtained in high radiochemical yield (> 98%) by reaction of fac-[99mTc(CO)3(H2O)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 invivo yielding fac-[99mTc(CO)3{HO(CH2)2NHCH2CH(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 = MeOCH2 (2), EtOCH2 (3), nPrOCH2(4)) and fac-[Re(CO)3{RNHCH2CH(pz)2}]Br (R = H (5), MeO(CH2)2 (6) HO(CH2)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 (κ3-N3) anchor ligands. Solution NMR studies have also shown that this κ3-N3 coordination mode is retained in solution for all complexes (2–7).

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