Novel radiopharmaceuticals: characterization, substitution kinetics and biological evaluation of tricarbonyl complexes of Rhenium(I)

[摘要] English: Over the past few years, significant interest has been shown in Rhenium and Technetium tricarbonyl complexes of the form fac-[M(L,L'-bid)(CO)3(X)]n (M = Tc(I) and Re(I), (L,L'-bid) = different donor atom bidentate ligands, X = range of monodentate ligands), as potential diagnostic and therapeutic radiopharmaceuticals, respectively. This is mainly due to the discovery of the fac-[M(CO)3(H2O)3]+ synthon with the inert fac- [M(CO)3]+ core and the labile water molecules. These main characteristics make the synthons very attractive for application in nuclear medicine. Overall, the idea of this study was to gain further insight into the chemistry, coordination and kinetic behaviour of complexes containing the fac-[M(CO)3]+ core. From this idea, it was decided to synthesize a few novel ligand systems. This include N-benzylindole- 2,3-dione, N,N'-bis(2-pyridylmethyl)-2-aminoethanol, N,N'-bis(2-pyridylmethyl)-2-aminopropanol, N,N'-bis(2-pyridylmethyl)-2-aminobutanol, N'-(2-(1H-imidazol-4-yl)ethyl)- N3,N3-bis(pyridine-2-ylmethyl)-propane-1,3-diamine, 2-(3-(bis(pyridin-2-yl)methyl)- amino)propylamino)-acetic acid, N-(2-(1H-imidazol-4-yl)ethyl)pyrrolidine-2-carboxamide, N'-(2-(1H-imidazol-4-yl)ethyl)benzohydrazide and N-(pyridin-2-ylmethyl)nicotinamide. Some of these ligands were successfully coordinated to the fac-[Re(CO)3]+ core as well. The ligand systems, as well as these Rhenium(I) compounds, were sent for in vitro testing. The ligand systems synthesized were designed with the idea to be potentially biologically active by itself as well. A range of tricarbonyl complexes, of the form fac-[Re(L,L'-bid)(CO)3X], were synthesized by using a wide variety of bidentate ligands (L,L'-bid), with systematically chosen donor atoms. The bidentate ligands include 2,2'-bipyridine-3,3'-dicarboxylic acid, 2,5-pyridinedicarboxylic acid, 8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, 5,7-dimethyl-8-hydroxyquinoline, tropolone, isatin, 5-nitroisatin, 5-(trifluoromethoxy)- isatin, benzohydroxamic acid, 3-hydroxyflavone, chrysin and bis(diphenylphosphino)- propylamine, X = variety of monodentate ligands and n = 0, 1. During the study, four 99mTc complexes were successfully synthesized, including fac- [99mTc(2,5-PicoH)(CO)3(H2O)], fac-[99mTc(Trop)(CO)3(H2O)], fac-[99mTc(Cl ox)(CO)3(H2O)] and fac-[99mTc(DMe-ox)(CO)3(H2O)]. We were unable to isolate the 99mTc compounds of five different ligand systems, even though the Rhenium analogues were successfully synthesized. This once again proved the similarities in chemistry of Rhenium and Technetium, but that this cannot always be assumed. The lability and mechanism of substitution of the methanol ligand by simple monodentate nuclephiles were evaluated. The methanol substitution reactions, between fac-[Re(2,5-PicoH)(CO)3(MeOH)], fac-[Re(Isa)(CO)3(MeOH)] and fac- [Re(Trop)(CO)3(MeOH)] and the variety of incoming ligands (bromide ions, iodide ions, pyridine, 4-dimethylaminopyridine, imidazole, thiocyanate ions, thiourea and 1-methyl-2- thiourea), all pointed towards an interchange associative or associative type mechanism, predicted from the negative ΔS�?values calculated. High pressure studies were performed and from the results, an interchange dissociative type mechanism was assigned, with a definite decrease in the reaction rate with an increase in pressure. These results once again proved the only way to unambiguously determine a reaction mechanism, is by means of the high pressure studies. For the first time ever, the water substitution reaction of a compound of the type fac-[Re(L,L'-bid)(CO)3(H2O)] was performed. The reaction between fac- [Re(Trop)(CO)3(H2O)] and thiocyanate ions were followed. Overall the water substitution reaction has larger k1 and K1 values compared to the corresponding methanol substitution reaction, therefore indicating a faster reaction and a more stable product. These are especially great results for the use in nuclear medicine. From the kinetic studies performed, excellent results were obtained of which one is the definite increase in reaction rate from N,O- to O,O'-donor bidentate ligand compounds. This was expected due to the increase in electron density on the metal centre and therefore the weakening of the Re-MeOH bond. The O,O'-donor bidentate ligands activate the Re(I) metal centre to an even greater extent, as was reported before. The '3+1' concept was proven, from the synthesis of fac-[Re(PMAEth-An)(CO)3][NO3], fac- [Re(PMAProp-His)(CO)3][NO3] and fac-[NEt4]/[Na][Re(NTA-An)(CO)3], by linking a biologically active ligand to the backbone of a tridentate ligand that is coordinated to the fac-[Re(CO)3]+ core. This leaves huge scope for potential radiopharmaceutical agents of this type. Four of the ten crystal structure reports in this study are monodentate substituted complexes, which serves as further confirmation of the kinetic end products.

[发布机构] University of the Free State