Furthermore, [18F]FPPDB substantially labeled NFTs and senile plaques in AD brain sections but not control brain sections. normal mice, [18F]FPPDB displayed higher uptake (4.28% ID/g at 2 min postinjection) into and washout (2.53% ID/g at 60 min postinjection) from the brain with time. On the basis of the chemical structure of FPPDB, further raises in selective binding to tau aggregates may lead RAF265 (CHIR-265) to the development of more useful probes for the imaging of NFTs in AD brains. Keywords:Alzheimer’s disease (AD), neurofibrillary tangles (NFTs), imaging, benzothiazole, PET Alzheimer’s disease (AD) is definitely a progressive neurodegenerative mind disorder associated with cognitive decrease, disorientation, and language impairment and is characterized by the presence of senile plaques (SPs) composed of -amyloid (A) peptides and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein.1At present, the medical diagnosis of AD depends on medical history and neuropsychological findings, and the early cognitive and behavioral symptoms of AD are often indistinguishable from normal signs of aging. Because a certain analysis of AD is based on the postmortem histopathological examination of SPs and NFTs, useful methods of evaluating the histopathological changes in vivo are strongly needed. The formation of SPs is considered an initial manifestation of AD. Therefore, considerable effort has focused on the development of imaging probes focusing on SPs for positron emission tomography (PET) and solitary photon emission computed tomography (SPECT). Among them, PET/SPECT probes such as IMPY,2SB-13,3PIB,4AZD2184,5FDDNP,6BAY94-9172,7AV-45,8and GE-0679have been tested clinically and shown the potential power of the in vivo imaging of SPs in the brain. Many other compounds with structural similarities have also been reported. Since the build up of NFTs is definitely highly correlated with symptoms of AD10,11and the detection of NFTs in the brain should lead to the early analysis of AD and the evaluation of severity and staging, RAF265 (CHIR-265) the development of NFT-selective binding probes is needed. However, there have been few reports within the development of PET/SPECT imaging probes focusing on NFTs. A earlier paper offers reported quinoline and benzimidazole derivatives as candidate probes for the imaging of NFTs in AD brains.12,13However, these derivatives showed affinity for both NFTs and SPs, suggesting that they may not be NFT-selective tracers. Therefore, to investigate the selective binding affinity for both NFTs and SPs, we recently developed radioiodinated compounds based on another chemical structure, a phenyldiazenyl benzothiazole (PDB) scaffold (Number1).14All of the PDB derivatives displayed high affinity for tau aggregates. PDB-3, having a dimethylamino group at position 4 of the phenyl group, showed the highest affinity (17.2-fold that for A142aggregates), indicating it to be a tracer with higher selective binding to tau aggregates than the quinoline and benzimidazole derivatives reported previously. However,125I-labeled PDB derivatives showed a relatively low uptake into and sluggish washout from the brain, suggesting high nonspecific binding, which would contribute to a high level of background noise. Since the sluggish washout of [125I]PDB derivatives in normal mice prevents imaging in vivo, the improved house of the PDB derivatives should make them better candidates for the study of tau aggregates. == Number 1. == Chemical structure of iodinated and fluoro-pegylated PDB derivatives. Earlier studies concerning uptake into and clearance from the brain points to high lipophilicity as one of the reasons for a sluggish washout.15,16We then planned to develop a novel PDB derivative with less lipophilicity by substituting iodine, which increases the lipophilicity of a compound, with fluorine for the preparation of PET tracers. Recent reports have introduced a new approach, fluoro-pegylation (FPEG) of the core structure, to labeling with18F.7,17,18Because this approach offers a simple and easy way to incorporate18F without any increase in lipophilicity, we selected FPEG for18F-labeling of the PDB scaffold. In the present study, we designed and synthesized a novel fluorinated ligand, (E)-4-((6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)diazenyl)-N,N-dimethylaniline (FPPDB, Number1) having a fluoro-polyethylene glycol part chain instead of iodine at position 6 of PDB-3, and evaluated its potential like a probe for the imaging NFTs in the brains in vivo. A new ligand, FPPDB, was prepared as layed out in Plan1A. A methoxy group of 2-amino-6-methoxybenzothiazole was converted to a hydroxy group using a HBr answer, which afforded1in a yield of 71.0%. To obtain RAF265 (CHIR-265) the backbone structure of PDB, we used a diazo coupling reaction withN,N-dimethylaniline to afford2. Thereafter, 2-[2-(2-chloroethoxy)ethoxy]ethanol was coupled with the OH group of2to obtain3. Fluorination of3to prepare5was accomplished using diethylamino sulfur trifluoride (DAST).18F-labeling of5was performed on a tosyl precursor (4) undergoing a nucleophilic displacement reaction with the fluoride anion (Scheme1B). Radiolabeling with18F was successfully performed within the FOS precursor to generate [18F]5([18F]FPPDB) having a radiochemical yield of 35% and radiochemical purity.