Design and Synthesis of Novel Lanthanide Chelates for Use in Magnetic Resonance Imaging (MRI)
thesisposted on 2012-03-21, 12:24 authored by Graeme James Stasiuk
This thesis reports a series of novel Ln-DO3A based complexes, modulation of emission intensity (Eu and Tb) has been achieved and relaxivity, r1, (Gd) has been shown. Propargyl-appended lanthanide complexes derived from DO3A, has a hydration state, q = 2. They undergo Cu(I) catalysed cycloaddition reactions with azides to form 1,2,3-triazole appended complexes: coordination of one of the triazole nitrogen atoms to the metal centre changes the local coordination environment and luminescence studies indicate a hydration state of q = 1. Propargyl-appended Ln(III) complexes show unanticipated reactivity towards NaN3 in the Cu(I) catalysed ‘click’ reaction yielding an unsubstituted 1,2,3-triazole. The resulting Eu(III) complex exhibits pH-responsive ¹H NMR and Ln(III) luminescence behaviour in the physiological pH range, consistent with deprotonation of the NH-acidic bound triazole. The coordination mode of the NH-triazole switches from NH-triazole bound in a pyridinic manner to bound in an anionic manner as a triazolide, while retaining a q = 1. This was demonstrated in luminescent studies of Eu(III) and Tb(III) complexes with a pKa ~ 7.5. Relaxation measurements on the Gd(III) analogue show a q =1 throughout the pH range, i.e. no change in hydration state. To overcome the unanticipated reactivity of NaN3 with propargyl-appended Ln(III) complexes, p-ethynylbenzyl-appended Ln(III) complexes were synthesised. These show promise as precursors for multimeric, self-associating and d-f hybrid complexes, via the Cu(I) catalysed cycloaddition or ‘click’ reaction. Luminescent studies show evidence of the formation of 1,2,3-triazoles that do not bind to the Ln(III) metal centre, with a hydration state q =1. These complexes have been applied in the synthesis of multimeric, self-associating and d-f hybrid compounds. Uridine was attached to a EuDO3A chelate via four different linkers. These complexes are precursors for an accumulation and activation strategy, developed as enzyme activated contrast agents. Neutral q = 1 Eu(III) uridine-DO3A based complexes were successfully synthesised and linked via a propyl, amide or 1,2,3-triazole unit.
Date of award2010-07-07
Awarding institutionUniversity of Leicester