Rhenium and technetium radio-isotope complexes linked to biologically active molecules

[摘要] English: Rhenium is the third row congener and 5d analogue of technetium. Technetium is the most widely used radionuclide in diagnostic imaging, thus it would be advantageous to explore the use of rhenium as a possible therapeutic radiopharmaceutical. The advantage of using rhenium instead, is that it is non-radioactive in its natural form, possessing similar properties as technetium. Their (rhenium and technetium) chemical behaviour is so similar that it is almost impossible for biological systems to differentiate between them. These similarities include size, shape, lipophillicity, dipole moment, charge and ionic mobility, thus forming complexes of the same geometry.The main attraction in the use of rhenium as a potential radiopharmaceutical agent is thefac-[Re(CO)3]+ moiety. Only a few crystal structures of the form, fac-[Re(O-O')(CO)3X],(O-O' = bidentate ligands and X being halides, monodentate ligands etc.) has been published. In 2012 only ten crystal structures containing O,O'- donor bidentate ligands have been introduced. Substitution kinetic studies using rhenium tricarbonyl complexes is still an under explored field. The principle aim in this study, was to synthesise complexes of the form, fac-[M(L,L')3(CO)3X] (M = Re, Tc; L,L' = O,O'- and N,O-donor bidentate ligands; X = Br-, Py, H2O). These bidentate ligands include compounds that are biologically active. In synthesising these complexes, two new rhenium(I) crystal structures, containing O,O'-donor bidentate ligands have been introduced. The bidentate ligand systems, used in this study was O,O' -donor ligand systems, acetylacetone (Acac), trifluoroacetylacetone (TFA), hexafluoroacetylacetone (HFA) and N,O-donor ligands, ephedrine (Eph) and 8-hydroxyl-quinoline (8-Quin). The following three 99mTc complexes were synthesised, fac-[99mTc(Acac)(CO)3(H2O)],fac-[99mTc(TFA)(CO)3(H2O)] and fac-[99mTc(HFA)(CO)3(H2O)] and their formation was established, using reverse phase thin layer chromatography (TLC). Their Rf values increased in the following order: fac-[99mTc(Acac)(CO)3(H2O)] (0.227) > fac-[99mTc(TFA)(CO)3(H2O)] (0.392) > fac-[99mTc(HFA)(CO)3(H2O)] (0.537), indicative of their solubility in 0.1% trifluoroacetic acid.In the substitution kinetic study, pyridine was used as the entering ligand to substitute the methanol ligand. Chapter 4 describes the characterisation of the synthesised compounds, using IR, UV/VIS, 1H-NMR as well as 13C-NMR. The complexes that were characterised by X-ray crystallography are: fac-[Re(TFA)(CO)3(Py)] and fac-[Re(HFA)(CO)3(Py)]. Both complexes crystallised out in the P21/c space group, with their RE-O'O bond distances at 2.135(3) Å and 2.117(3) Å, for fac-[Re(TFA)(CO)3(Py)], and 2.127(2) Å and 2.1376(19) Å for fac-[Re(HFA)(CO)3(Py)].A trend was observed in the IR data in terms of the stretching frequencies (VCO), with an increase in the VCO (caused by the influence of the electron withdrawing flourine atoms) in the following order: fac-[Re(Acac)(CO)3(OH2)] (2015 cm-1, 1907 cm-1, 1879 cm-1) < fac-[Re(TFA)(CO)3(OH2)] (2018 cm-1, 1895 cm-1, 1878 cm-1) < fac-[Re(HFA)(CO)3(OH2)] (2025 cm-1, 1917 cm-1, 1888 cm-1), indicating a decrease in the electron density surrounding the metal centre and thus a decrease in the CO π-back bonding, causing the Re-OH2 bond to shorten. The kinetic rate for the substitution of the methanol ligand (at 25°C) yielded the following results: fac-[Re(Acac)(CO)3(CH3OH)] (k1 = 13.7(1) x 10-3 M-1.s-1) > fac-[Re(TFA)(CO)3(CH3OH)] (k1 = 0.35(3) x 10-3 M-1.s-1) > fac-[Re(HFA)(CO)3(CH3OH)] (k1 = 0.17(3) x 10-3 M-1.s-1). This difference in the kinetic rate is highly affectd by the electron withdrawing fluorine atoms, attached to the coordinated bidentated ligands of fac-[Re(TFA)(CO)3(CH3OH) and fac-[Re(HFA)(CO)3(CH3OH)]. The activation parameters obtained were as follows: ∆H�?= 64(1) kJ mol-1 and ∆S�?= -65(5) J K-1 mol-1, with the negative ∆S�?value indicating towards an interchange associative type mechanism.A cell study performed on oesophageal cancer cell line with fac-[Re(Acac)(CO)3(Py)] (IC50 = 14.92) and fac-[Re(TFA)(CO)3(Py)] (IC50 = 16.13), using MTT assay protocol did not yield promising results.

[发布机构] University of the Free State