Design And Synthesis Of Responsive Molecular Probes For ¹⁹F Magnetic Resonance And Their Applications For Biological Detection And Imaging

Modern research of life science shows that almost all processes and phenomena of life can be understood via investigating corresponding molecular processes.Nowadays,molecular imaging(MI)has emerged as an important means for acquiring the information at the molecular level,which facilitates the exploration of molecular processes.Magnetic resonance imaging(MRI)is a powerful technique of MI.With the development of MRI-related techniques,the drawback of strong background interference in 1H MRI comes to the attention of the research community.As a result,19F MRI has been appealing during the past ten years because of its advantages,especially negligible background.The introduction of this thesis briefly discusses the basic concepts and principles of MRI in the perspective of information acquisition and summarizes the current advancement of 19F MRI and the basis of probe design through literature analysis.The rest of this thesis describes the exploitation of the paramagnetic relaxation enhancement(PRE)effect to construct responsive molecular probes for 19F MRI to detect small biological molecules/ions:1.Based on the redox pair of Mn(Ⅲ)/(Ⅱ),a pair of Mn complexes Mn(Ⅲ)/(Ⅱ)-L1 with high 19F content were synthesized as reversible redox responsive 1H/19F MRI probes to detect GSH/H2O2 in aqueous solution.When Mn(Ⅲ)-L1(Probe 1)is reduced to Mn(Ⅱ)-L1(Probe 2),the 19F MRI signal is weak due to the strong PRE effect of the Mn2+ ion,which results in the very short T2 of 19F nuclei;whereas Mn(Ⅱ)-L1 possesses near 4-fold greater r1 for 1H MRI than Mn(Ⅲ)-L1,leading to strong T1-weighted 1H MRI signal.Conversely,when Mn(Ⅱ)-L1 is oxidized,the 19F MRI signal of Mn(Ⅲ)L1 is strong because of suitable T1 and T2 relaxation times of 19F.At the same time,1H MRI signal is attenuated.It is noteworthy that Mn(Ⅲ)-L1 has about 8-fold greater 19F MRI signal intensity than L1,owing to the appropriate PRE effect of the Mn3+ ion to 19F nuclei.2.A strategy of competitive coordination was used to construct a 1H/19F MRI molecular probe for selective detection of Ca2+ ions.A 19F-containing ligand L2,which has high chelating constant with Ca2+ ions,was synthesized and chelated with Mn2+ions to form complex Mn(Ⅱ)-L2(Probe 3).The 19F MRI signal of Mn(Ⅱ)-L2 is weak as the T2 of 19F nuclei was shortened dramatically by the PRE effect of the paramagnetic Mn2+ ion.Mn2+ ions can be specifically replaced by Ca2+ ions via competitive coordination,leading to the increase of distance between Mn2+ ions and 19F nuclei and the recovery of 19F MRI signal.Meanwhile,due to the increase of the number of coordination water molecules,free Mn2+ ions show more than 2-fold higher r1 for 1H MRI than Mn(Ⅱ)-L2,which brings about brighter 1H MRI signal.3.Inspired by the success of Probe 1 and Probe 3,we designed a 19F-containing complex,which has two paramagnetic metal ions(Ma and Mb),as a highly sensitive 19F MRI molecular probe(Probe 4)for selective detection of Zn2+ions.The 19F MRI signal of Probe 4 is weak due to the strong PRE effects of Ma and Mb(MnⅢ).When Ma is specifically replaced by Zn2+ ions via competitive coordination,enhanced 19F MRI signal could be observed because Mb could exert suitable PRE effect on 19F nuclei like the Mn3+ion does in Probe 1.In summary,we designed and synthesized several responsive 19F MRI molecular probes by modulating the effects of paramagnetic metal ions on 19F MRI signals,and studied their performance for biological detection and imaging of specific biological small molecules/ions,which could be enlightening for the construction of bioresponsive 19F MRI molecular probes in the future.