Development of Triphenylmethane Dyes for In Vivo Fluorescence Imaging of Aß Oligomers.

Detection of amyloid ß (Aß) oligomers, regarded as the most toxic aggregated forms of Aß, can contribute to the diagnosis and treatment of Alzheimer's disease (AD). Thus, the development of imaging probes for in vivo visualization of Aß oligomers is crucial. However, the structural uncertainty regarding Aß oligomers makes it difficult to design imaging probes with high sensitivity to Aß oligomers against highly aggregated Aß fibrils. In this study, we developed Aß oligomer-selective fluorescent probes based on triphenylmethane dyes through screening of commercially available compounds followed by structure-activity relationship (SAR) studies on cyclic or acyclic 4-dialkylamino groups. We synthesized 11 triarylmethane-based Aß oligomer probe (TAMAOP) derivatives. In vitro evaluation of fluorescence properties, TAMAOP-9, which had bulky 4-diisobutylamino groups introduced into three benzenes of a twisted triphenylmethane backbone, showed marked fluorescence enhancement in the presence of Aß oligomers and demonstrated high selectivity for Aß oligomers against Aß fibrils. In docking studies using the Aß trimer model, TAMAOP-9 bound to the hydrophobic surface and interacted with the side chain of Phe20. In vitro section staining revealed that TAMAOP-9 could visualize Aß oligomers in the brains of AD model mice. An in vivo fluorescence imaging study using TAMAOP-9 showed significantly higher fluorescence signals from the brains of AD model mice than those of age-matched wild-type mice, confirmed by ex vivo section observation. These results suggest that TAMAOP-9 is a promising Aß oligomer-targeting fluorescent probe applicable to in vivo imaging.

In Vivo Near-Infrared Fluorescence Imaging Selective for Soluble Amyloid ß Aggregates Using y-Shaped BODIPY Derivative.

Soluble amyloid ß (Aß) aggregates, suggested to be the most toxic forms of Aß, draw attention as therapeutic targets and biomarkers of Alzheimer's disease (AD). As soluble Aß aggregates are transient and diverse, imaging their diverse forms in vivo is expected to have a marked impact on research and diagnosis of AD. Herein, we report a near-infrared fluorescent (NIRF) probe, BAOP-16, targeting diverse soluble Aß aggregates. BAOP-16, whose molecular shape resembles "y", showed a marked selective increase in fluorescence intensity upon binding to soluble Aß aggregates in the near-infrared region and a high binding affinity for them. Additionally, BAOP-16 could detect Aß oligomers in the brains of Aß-inoculated model mice. In an in vivo fluorescence imaging study of BAOP-16, brains of AD model mice displayed significantly higher fluorescence signals than those of wild-type mice. These results indicate that BAOP-16 could be useful for the in vivo NIRF imaging of diverse soluble Aß aggregates.

Synthesis and evaluation of novel radioiodinated phenylbenzofuranone derivatives as α-synuclein imaging probes.

α-Synuclein (α-syn) aggregates are major components of pathological hallmarks observed in the human brain affected by neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. It is known that α-syn aggregates are involved in the pathogenesis of these neurodegenerative diseases. However, detailed mechanisms have not been fully elucidated. Therefore, the development of radiolabeled imaging probes to detect α-syn aggregates in vivo may contribute to early diagnosis and pathophysiological elucidation of neurodegenerative diseases affected by α-syn aggregates. In the present study, we designed and synthesized four radioiodinated phenylbenzofuranone (PBF) derivatives: [123/125I]IDPBF-2, [123/125I]INPBF-2, [123/125I]IDPBF-3, and [123/125I]INPBF-3, as candidates for α-syn imaging probes. All four compounds exhibited high binding affinity for recombinant α-syn aggregates in an inhibition assay. However, brain uptake of all four compounds was insufficient to achieve α-syn imaging in vivo. Considering the results of this study, while further structural modifications are required to improve brain uptake, it is suggested that PBF derivatives show fundamental characteristics as α-syn imaging probes.

Hexagonal supramolecular architectures from ferrocenium cations incorporating [Ni(mnt)2]- columns: structures and properties of [alkylferrocene][Ni(mnt)2]- charge-transfer complexes (mnt=maleonitriledithiolate).

The crystal architecture, magnetic properties, and thermodynamic properties of [n-butylferrocene][Ni(mnt)2] (1), [tert-butylferrocene][Ni(mnt)2] (2), [1,1'-diethylferrocene][Ni(mnt)2] (3), and [1,1'-diisopropylferrocene][Ni(mnt)2] (4) were investigated (mnt=maleonitriledithiolate). These complexes exhibit a unique supramolecular structure in which the ferrocenium cations constitute honeycomb-like assembled structures surrounding columns of the anions. For 1, the cations form a dimer through a very short intermolecular ferrocene-ferrocene distance of 3.28 A, which mediates an antiferromagnetic interaction with a singlet-triplet energy gap of 5 K. First-order phase transitions occur in 1-3 at 364, 361, and 350 K, respectively, accompanied by thermal hysteresis.