Partner und Internationale Organisationen
(Englisch)
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AT, BE, CY, CZ, FI, FR, DE, EL, HU, IT, LV, NL, NO, PL, PT, RO, SK, ES, CH, UK
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Abstract
(Englisch)
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Introduction: Magnetic Resonance Imaging (MRI) is one of the most powerful techniques in the diagnostic medicine and biomedical research. Contrast Agents based on Gd(III) chelates are now used in more than 30% of the exams with MRI. Nowadays, even if currently available contrast agents for routine clinical examinations are safe and good enhancers, they are unspecific towards the idenfication of specific tissue. Aim: The goal of this work is the development of MRI contrast agents with the ability of selective targetting to tissues. To reach this goal a careful selection of targets, as well as an optimisation of the following parameters are mandatory: water exchange rate, rotational correlation time and electronic correlation time. Results: For imaging blood-pool and cardiovascular disorders, high molecular weight contrast agents could be administrated intravenously. Macromolecular agents ensure a long presence in the intravascular space and have been investigated for this purpose. Therefore we synthesized two potential Gd(III)-based MRI contrast agents [Gd(DOTA2C14)(H2O)] and [Gd(DOTA3C14)(H2O)2]. These DOTA-like chelates bearing two, respectively three alkyl side chain with C14, capable of micellar self-organisation. The CMC (critical micellar concentration) of [Gd(DOTA2C14)(H2O)] was 3.6·10-6 M, the CMC of [Gd(DOTA3C14)(H2O)2] could not be measured (estimation: ~10-11 M), because of low solubility. Relaxivities could not be determined because of low solubility of the complexes in water. To obtain high relaxivities based on improved water exchange rates for Gd(III) chelates we synthesized bifunctional versions of the macrocycle TRITA (1,4,7,10-tetraazacyclotridecane-1,4,7,10 tetraacetic acid). [(Gd-TRITA)(H2O)]+ presents optimal water exchange rate (k298 = 270·106 s-1) compared to [(Gd-DOTA)H2O)]- (k298 = 4.1·106 s-1). Modifications on the backbone of the chelate will allow the coupling of TRITA to biomolecules like biotin, peptides or monoclonal antibodies (mAb). On the way to a targetted MRI contrast agent we have to increase the specific activity to get a higher concentration of Gd(III) to the site of interest. The need for improvement and amplification strategies is of outmost importance because typical target concentration are in the pico- and nanomolar range rather than in the micromolar range (1 to 50 µM) necessary for MRI contrast enhanced imaging. We synthesized a tree-like poly-DOTA derivative (DOTA4-Apg3-Sar5-TATE) which binds with high affinity to the somatostatin receptor subtype 2 (sst2) and shows the same rate of internalization (21.5 ± 2.3%) compared to DOTA-TATE. The relaxivity profile of [(Gd-DOTA)4-Apg3-Sar5]-TATE shows a increased relaxivity (r1 = 8.9 mM-1s-1 /20 MHz/37°C per Gd) compared to DOTAREM® ([(Gd-DOTA)H2O]-; r1 = 3.83 mM-1s-1 /20 MHz/37°C). This is due to the increase of the rotational correlation time from 77 ps to 490 ps.
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