Published: March 21, 2011 r2011 American Chemical Society 2225 dx.doi.org/10.1021/jm101404k | J. Med. Chem. 2011, 54, 2225–2240 ARTICLE pubs.acs.org/jmc Synthesis and StructureAffinity Relationships of Novel Dibenzylideneacetone Derivatives as Probes for β-Amyloid Plaques Mengchao Cui, †,‡ Masahiro Ono,* ,† Hiroyuki Kimura, † Boli Liu, ‡ and Hideo Saji* ,† † Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan ‡ Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China b S Supporting Information ’ INTRODUCTION Alzheimer's disease (AD) is an irreversible, progressive brain disorder that accounts for the majority of dementia cases. Histopathologically, AD is characterized by β-amyloid (Aβ) plaques composed mainly of mis-folded Aβ peptides and neuro- fibrillary tangles (NFTs) containing hyperphosphorylated τ protein. 1,2 However, the precise molecular mechanisms leading to AD remain unknown. Several theories have arisen, with the amyloid cascade hypothesis perhaps the most prominent. 3,4 Moreover, a refined version of the amyloid cascade hypothesis proposes that soluble Aβ peptides (soluble oligomers or proto- fibrils), not mature Aβ plaques, exert toxic effects on neuronal cells. 5,6 The clinical diagnosis of AD is primarily based on neurological observations and patient history and is often difficult and unreliable. Although there is a lack of correlation between cognitive decline and elevated levels of Aβ plaques in the brain, 7,8 several reports indicate that overaccumulation of Aβ peptides initiates a sequence of events that lead to neurodegeneration. 9,10 Therefore, Aβ plaques could be considered a biomarker for the early diagnosis of AD. With the assistance of nuclear imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), radionuclide-labeled agents targeting Aβ plaques in the brain may greatly facilitate the diagnosis of AD. 11,12 Over the past 10 years, several agents for imaging Aβ plaques have been tested in humans (Figure 1). Pittsburgh compound B, 2-(4 0 -[ 11 C]methylaminophenyl)-6- hydroxybenzothiazole ([ 11 C]PIB), is, to date, the most widely used PET radioligand for amyloid imaging 13,14 and clearly distinguishes between AD and control cases. However, the short half-life of carbon-11 (20.4 min) limits the potential clinical use of this agent. Great efforts have been made to develop imaging agents labeled with a longer half-life isotope, fluorine-18 (109.4 min). An analogue of PIB, [ 18 F]-2-(3-fluoro-4-(methylamino)phenyl) benzo[d]thiazol-6-ol ([ 18 F]GE-067), 15 and the stilbene deriva- tives [ 18 F]-4-(N-methylamino)-4 0 -(2-(2-(2-fluoroethoxy)ethoxy) ethoxy)-stilbene ([ 18 F]BAY94-9172) 16 and [ 18 F]-(E)-4-(2- (6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N- methylaniline ([ 18 F]AV-45) 17,18 are under commercial develop- ment for the mapping of Aβ plaque burden in living brain tissue. In addition, [ 123 I]-6-iodo-2-(4 0 -dimethylamino-)phenyl-imidazo [1,2]pyridine ([ 123 I]IMPY) 1921 is the first SPECT probe to be evaluated in humans. The preliminary clinical data showed a poor signal-to-noise ratio, making it difficult to distinguish AD patients. Currently, some research groups have continued to develop more useful probes for the SPECT imaging of cerebral Aβ plaques. 2224 Almost all of the agents evaluated in humans have been developed based on thioflavin T (ThT) and Congo Red (CR), dyes used for Aβ plaques in sections of AD brain. Aβ plaques are known to have various binding sites for ligands, 25 and numerous Aβ-binding compounds besides ThT and CR derivatives have been reported. The application of these new compounds to PET/SPECT imaging should contribute to the development of new probes with improved properties including higher affinity for Aβ plaques and less nonspecific binding in the white matter of the brain. Indeed, we have found that flavonoids such as Received: October 28, 2010 ABSTRACT: A new and extensive set of dibenzylideneacetone derivatives was synthesized and screened for affinity toward Aβ 142 aggregates. Structureactivity relationships revealed the binding of dibenzylideneacetones to be affected by various substituents. The introduction of a substituent group in the ortho position reduced or abolished the binding. However, the para position was highly tolerant of sterically demanding substitutions. Three radioiodinated ligands (6, 70, and 71) and two 18 F fluoro- pegylated (FPEG) ligands (83 and 85) were prepared, all of which displayed high affinity for Aβ 142 aggregates (K i ranging from 0.9 to 7.0 nM). In biodistribution experiments, they exhibited good initial penetration (1.59, 4.68, 4.56, 4.13, and 5.15% ID/g, respectively, at 2 min) of and fast clearance from the brain. Autoradiography with sections of postmortem AD brain and transgenic mouse brain confirmed the high affinity of these tracers. These preliminary results strongly suggest the dibenzylideneacetone structure to be a potential new scaffold for β-amyloid imaging probes.