Copper-based radiopharmaceuticals for diagnostic imaging of Alzheimer’s disease

© 2017 Dr. Lachlan Eion McInnesAlzheimer’s disease (AD) is characterised by the presence of extracellular cerebral plaques, comprised mostly of the aggregated amyloid-beta (Abeta) peptide, and intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tubulin associating unit (tau). A radiotracer that can bind specifically to either of these deposits would allow estimation of the burden of these deposits in suspected AD patients and assist in diagnosis and in the development of disease modifying therapies. A potential tracer for either Abeta or tau must be sufficiently chemically stable in vivo and able to cross through the blood-brain barrier (BBB). Copper has a range of useful isotopes for diagnostic applications. In particular, the positron (beta+) emitting isotopes 61Cu (beta+, t1/2 = 3.4 h), 62Cu (beta+, t1/2 = 9.8 min) and 64Cu (beta+, t1/2 = 12.7 h) are able to be integrated into essentially planar, lipophilic complexes and are able to be visualised by positron emission tomography (PET). Copper complexes based on the hybrid thiosemicarbazone-pyridylhydrazone (TPH) ligands form lipophilic, and a sufficiently stable coordination environment for Cu(II) while allowing functionalisation of the pyridyl group to include a targeting motif that can be tailored to the desired target. A series of complexes and their corresponding ligands have been synthesised and characterised that target Abeta using the N,N-dimethylaminostyrylpyridine targeting group ([CuL7,9-13]) and a novel pyridyl-4-vinylpyridyl core ([CuL14]. Both targeting groups show good binding to amyloid-plaques in human brain tissue. The pyridyl-4-vinylpyridyl-based [64Cu][CuL14] complex could be formed in high radiochemical purity under mild conditions and is a promising candidate for pre-clinical biodistribution studies to assess blood-brain barrier (BBB) permeability. The TPH framework has the potential to be modified to integrate a range of potential targeting groups for Abeta. A family of TPH complexes ([CuL15-22]) and corresponding ligands containing the benzofuran motif as a potential Aβ plaque targeting group have been synthesised and characterised. The most promising of these candidates is [CuL20], which interacts with both fibrillar and plaque forms of Abeta and has been shown greater selectively than the N,N-dimethylaminostyrypyridyl-based complex [CuL7] using laser-ablation inductively coupled plasma mass spectrometry. Initial biodistribution studies indicate that [64Cu][CuL20] is able to cross the BBB in appreciable amounts (1.54 ± 0.60% Injected Dose/gram of tissue (ID/g) at 2 minutes post injection). The development of radiotracers specific to aggregated tau are highly desirable from a diagnostic perspective. Tau deposition is thought to more closely follow the progression of symptoms in AD. To develop TPH complexes targeted to tau, a series of complexes ([CuL23-26]) and their corresponding ligands featuring the pyridylquinoline motif were synthesised and characterised. It was found that selectivity for tau could be modulated by the introduction of more sterically bulky substituents on the periphery of the TPH chelate. The most promising of these candidates [CuL26] has been selected for further evaluation to determine BBB permeability and investigate any off-target binding