O'Halloran, Mark (2002) Synthesis of dendritic gadolinium complexes with enhanced relaxivities. Doctoral thesis, Durham University.
This thesis deals with the synthesis of dendritic gadolinium complexes based on DOTA, with a view to obtaining enhanced relaxivities. Li addition to the inherently long electronic relaxation time and high paramagnetic moment of the gadolinium (III) ion, the speed of rotation of its complexes in solution is a decisive parameter in the determination of the relaxivity. This parameter is dependent on the molecular mass of the complex. Initially, the enantioselective synthesis of novel a-substituted analogues of DOTA was attempted but was not successful due to difficulties encountered in attaining the tetraalkylation of cyclen and the purification of the products obtained. Therefore, further studies were carried out based on the known [Gd(gDOTA)]" system. The synthesis of three medium M(_W) dendrons, each with a focal primary amino group was carried out. Their structures may be described as dendrimeric analogues of poly(ethylene glycol). Two of these structures were successfully coupled to the gadolinium (III) chelate, [Gd.gDOTA]. The acid-catalysed epimerisation of the statistical distribution of stereoisomers yielded solely the (RRRR)/(SSSS) isomeric pair. This system had previously been shown to undergo fast water exchange. The coupling and deprotection procedure yielded paramagnetic dendritic complexes with molecular weights of 2013 and 3535.Relaxivity measurements were carried out on these systems and the results showed significantly higher relaxivities of 18 and 21 mM(^-1) s(^-1) respectively, compared with a value of 7.8 mM(^-1) s(^-1) for the parent compound. Examination of NMRD profiles for the larger system showed a decrease in the rotational correlation time to 310 ps at 298 K, as expected. However, this was accompanied by an increase in the inner-sphere water exchange lifetime to 570 ns at 298 K. Therefore, although an improvement in relaxivity was obtained through a coupling to the slower rotation of the system in solution, this enhancement was limited by the accompanying decrease in the rate of water exchange. The best fitting procedure of the NMRD profiling procedure revealed the presence of 8 second-sphere water molecules at an average distance of 4Å. The second sphere contribution was shown to be the dominant contributor to the overall relaxivity. This accounted for >50% of the increased relaxivity.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||13 Sep 2012 15:49|