Development of an Alzheimer Imaging Agent

The amyloid hypothesis is a major theory to explain the etiology of Alzheimer Disease. The amyloid hypothesis states that plaque Aβ aggregated depositions, or partially aggregated soluble Aβ, trigger a neurotoxic cascade resulting in AD pathology of occurrence of amyloid plaques and neurofibrillary tangles (NFT). One recent hypothesis states that amyloid-β aggregation and deposition triggers a process of formation of paired helical filaments of tau that leads to neuronal loss. However, the correlation between Aβ plaques and NFT of tau is still to be deciphered Plaques and Aβ oligomers act as primary source for the start of the amyloid cascade, and interfering with Alzheimer might thus involve their regulation. The plaques are known to contain high concentrations of metals and especially Cu, Zn and Fe. Although the overall brain concentration of these metals is normal they are concentrated in pockets of Aβ aggregates. In this work, molecule I-L2b (N'-[(5-iodopyridin-2-yl)methyl]-N,N-dimethylbenzene-1,4-diamine), inspired from stilbene’s Aβ interaction and clioquinol’s metal chelation properties, was tested for toxicity in different lines of human cells at the concentrations needed for imaging. The interaction of the compound with metals and Aβ was also studied via binding properties, selectivity, complexation and its effect on aggregation. I-L2b molecules 15 and 18 have iodine substituent at 5th and 6th position of the pyridine. This is utilized to our advantage to form a potential imaging agent by synthesizing a stannylated precursor of our compound which is radiolabelled using radioactive isotope of Iodine I-123, half-life 13.2 hours and used for SPECT imaging to study its distribution with in the body of mice. The iodination reaction was first optimized under cold (non-radioactive) conditions. Several different hot reactions with radioactive iodine were then tested and different radiolabelled products obtained. After separation and purification, single photon emission computed tomography (SPECT) was performed in mice. The isolated radiolabelled molecule was introduced in two mice and low brain uptake was observed and one of the mice perished during first imaging cycle. In future, we will utilize these imaging results to repeat the animal study with better quality controls and eliminate possible reasons for toxicity of brain dose and low brain uptake