The objective of this SBIR program is to develop new dendrimeric paramagnetic contrast agents for use in magnetic resonance imaging (MRI). Dendrimeric contrast gents are known to exhibit very high proton relaxivity enhancement. Attachment of paramagnetic metal ions to dendrimers have been used successfully for the imaging of the heart, liver, vascular system, and kidneys. In our approach, new ligands which strongly bind gadolinium (III). These new contrast agents will exhibit very high proton relaxation enhancement and high tissue contrast due to the combination of the unique structure of the dendrimers and the high concentration of gadolinium(III) ions on each derivatized dendrimer molecule. The binding affinity for gadolinium by these new dendrimeric ligands will be determined as well as the spin-lattice relaxation (T1) and the spin-spin relaxation times (T2). To demonstrate the feasibility in Phase I, we will prepare dendrimers with molecular weights between 5,000 and 661,000. Gadolinium (III) chelating ligands with high binding affinities [e.g. diethylenetriamine-pentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-N,N', N"""""""", N'""""""""-tetraacetic acid (DOTA)] will be linked to the dendrimers and the proton relaxivities (R1 and R2) of these new gadolinium(III) complexes determined to investigate their potential as MRI contrast agents. The stability of these new contrast agents will be investigated to determine the thermodynamic stability of the gadolinium(III)-ligand complexes. In Phase II we will examine the in vivo stability, excretability, biodistribution, and toxicity of these new dendrimer paramagnetic contrast agents. In addition, the dependance of the proton relaxivity on the molecular structure of these new materials will be examined.
The development of new imaging agents will enhance MRI as a tool for non-invasive imaging by allowing better contrast between different types of tissue and reducing or eliminating problems with existing imaging agents including toxicity, stability and excretability. N improved class of imaging agents as the potent to be used in all radiology clinics offering MRI. It is anticipated that the best route to commercialization for these new agents will be in partnership with the companies who currently market imaging agents.
