This dissertation, "Lanthanide Complexes for Magnetic Resonance Imaging (MRI) Contrast Agents and Luminescent Sensors" by Cong, Li, 李聰, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled LANTHANIDE COMPLEXES FOR MAGNETIC RESONANCE IMAGING (MRI) CONTRAST AGENTS AND LUMINESCENT SENSORS Submitted by Li Cong for the degree of Doctor of Philosophy at The University of Hong Kong in June 2004 Magnetic resonance imaging (MRI) and bioluminescence imaging are widely used in medical diagnosis. There is a need to develop MRI contrast agents and 3+ 3+ luminescence sensors with higher sensitivity and specificity. Novel Gd and Tb complexes endowed with different functionalities have been synthesized and studied. In this work, a series of general and straightforward methods for the preparation of mono, 1,4 bis and tris N-alkylation of cyclen in high yields and with unprecedented regioselectivity were developed. These protocols are useful in introducing different functional groups to the 1,4,7,10-tetraazacyclododecane (cyclen) in a single step without the use of unnecessary protecting groups. For example, the functionalised 1,4,7-tris-(acetic acid)-1,4,7,10-tetraazacyclododecane (DO3A) derivatives that used to be prepared by multiple steps can now be achieved in two simple steps with attractive features such as high yield, operational convenience and cost economy. 3+ The novel mononuclear Gd polyaminocarboxylates based on cyclen, GdL1- GdL7, were synthesized. Functional groups, such as crown ethers with different ring sizes, β-D-glucopyranose, guanidinium and quinine alkylated diaza-18C6, were introduced into these complexes to achieve target-specificity. The synthesis, structural 1 13 characterization measured by single crystal X-ray analysis, H and C NMR, ESI-MS, HRFAB-MS and elemental analysis, luminescence-lifetime measurements, the relaxometric investigations of the complexes by nuclear magnetic resonance 17 dispersion (NMRD) profiles, variable-temperature O NMR transverse relaxation and pH dependence relaxivity, in vivo MRI studies and in vitro toxicity studies were 3+ discussed. Relaxivities of the four Gd complexes, GdL1, GdL3, GdL5 and GdL6 -1 -1 -1 -1 are in the descending order of GdL1 (9.65 mM s ) > GdL3 (9.36 mM s ) > GdL6 -1 -1 -1 -1 (7.34 mM s ) > GdL5 (3.75 mM s ) measured at 20 MHz and 25C. Compared to -1 -1 the commercially available contrast agents [Gd(DOTA)(H O)] (4.74 mM s ) and -1 -1 [Gd(DO3A)(H O) ] (5.72 mM s ) with two bound water molecules, GdL1, GdL3 2 2 and GdL6 showed much higher relaxivity. The most striking result is the water molecule exchange lifetime of GdL1, which was measured as 55 ns, very close to the optimum value of 20-30 ns in theory. GdL1, GdL3 and GdL6 also demonstrated outstanding performances in the MRI studies based on small animals. The maximal renal and hepatic intensity enhancements (IE) induced by GdL1 were 200% and 105% respectively above the control level, and much higher than those of Gd-DOTA at 123% and 70%. Moreover, GdL1 and GdL3 afforded much longer resident lifetimes in the kidney cortex and liver parenchyma. It is noteworthy that GdL1 showed obvious target-specificity to liver tissue. The maximal hepatic IE induced by GdL1 with low dosage (90%, 0.03 mmol/kg) is even higher than that of Gd-DOTA with three times dosage (70%, 0.1 mmol/kg). Furthermore, an in vitro MTT assay confirmed that the cytotoxicity of GdL1 is quite low even at high concentration (10 mM). The luminescent properties of TbL1, TbL3 and TbL7 were investigated in aqueous solution. TbL