Technetium complexes for diagnostic imaging of amyloid-beta plaques to assist in the diagnosis of Alzheimer's disease

© 2014 Dr. David John HayneThis thesis is not authorised to be made available in the Baillieu Reading Room until December 2016The pathological hallmarks of Alzheimer’s disease (AD) include extracellular plaques, primarily composed of aggregated Aβ peptide, and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. As cerebral Aβ plaque formation can precede the clinical symptoms of AD by decades, in vivo detection of Aβ plaques could assist in accurate diagnosis. The nuclear imaging modality of Single Photon Emission Computed Tomography (SPECT) is a widely available technique that uses the most popular radionuclide in nuclear imaging, technetium-99m. A probe that incorporates 99mTc and allows in vivo evaluation of Aβ plaque burden would be of great clinical utility. A series of tridentate ligands are presented that coordinate to the fac-[M(CO)3]+ core (M = Re/⁹⁹ᵐTc). A pendant group based on the trans-stilbene motif was attached via a small linker to facilitate binding of complexes to Aβ aggregates. Both neutral and monocationic complexes were synthesised by using ligands containing a tertiary amine donor combined with carboxylate and pyridyl or two pyridyl donating groups respectively. Binding of fac-[Re(CO)3Lx] complexes to Aβ plaques was assessed using human brain tissue. Binding to Aβ plaques only occurred for complexes that had a dimethylamino substituent connected to the trans-stilbene pendant group. The tridentate ligands coordinate efficiently at the no carrier added level with selected ⁹⁹ᵐTc complexes used for further animal model experiments. Bidentate 1,4-substituted pyridyl-1,2,3-triazole ligands for coordination to fac-[⁹⁹ᵐTc(CO)3]+ were also investigated. A cyclic peptide (cyclic-RGDfK) served as a model for incorporation of other biomolecules in the future. The type of linker for peptide conjugation affected ligand coordination. Ligands functionalised with an isothiocyanato group via a polyether chain formed the desired ⁹⁹ᵐTc complexes in high radiochemical purity. As a bidentate ligand is unable to exchange with all three water ligands of [⁹⁹ᵐTc(CO)3(H2O)3]+, exchange of the final water ligand was accomplished with pyridine, forming a monodentate ligand in a [2+1] ligand complex. A series of tetradentate ligands were synthesised for the formation of neutral complexes by triple deprotonation upon coordination to [MO]3+ (M = Re/⁹⁹ᵐTc). Synthesis and evaluation of rhenium complexes with ligands containing either a N4 or N3O donor atom set led to the selection of a diamido ligand containing the N3O donor atom set for further development. Incorporation of a styrylpyridine functional group enabled the complex to bind to Aβ plaques and also supplied a pyridyl donor group for coordination to the metal. Further development saw the synthesis and preliminary evaluation of the corresponding [⁹⁹ᵐTcO]3+ complex