2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Amyloid-Neuropathies

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition.

Topics: Algorithms; Alzheimer Disease; Amyloid; Amyloid Neuropathies; Aniline Compounds; Benzothiazoles; Cerebral Cortex; Cohort Studies; Computer Simulation; Cross-Sectional Studies; Humans; Individuality; Longitudinal Studies; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Thiazoles

Novel dibenzothiazole derivatives were synthesized and evaluated as amyloid-imaging agents. In vitro quantitative binding studies using AD brain tissue homogenates showed that the dibenzothiazole derivatives displayed high binding affinities with K(i) values in the nanomolar range (6.8-36 nM). These derivatives are relatively lipophilic with partition coefficients (logP oct) in the range of 1.25-3.05. Preliminary structure-activity relationship studies indicated dibenzothiazole derivatives bearing electron-donating groups exhibited higher binding affinities than those bearing electron-withdrawing groups. A lead compound was selected for its high binding affinity and radiolabeled with [(125)I] through direct radioiodination using sodium [(125)I] iodide in the presence of Chloramine T. The radioligand (4-[2,6']dibenzothiazolyl-2'-yl-2-[(125)I]-phenylamine) displayed moderate lipophilicity (logP oct, 2.70), very good brain uptake (3.71+/-0.63% ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.78% and 0.43% ID/g at 30 and 60 min, respectively). These studies indicated that lipophilic dibenzothiazole derivatives represent a promising pharmacophore for the development of novel amyloid-imaging agents for potential application in Alzheimer's disease and related neurodegenerative disorders.

Topics: Alzheimer Disease; Amyloid Neuropathies; Animals; Benzothiazoles; Brain; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Humans; Indicators and Reagents; Iodine Radioisotopes; Magnetic Resonance Spectroscopy; Mice; Permeability; Radioligand Assay; Radionuclide Imaging; Radiopharmaceuticals; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet