Nonpolar selective emission (NPSE) of carbonyl-bridged rhodols.

Polarity-responsive luminophores (PRLs), whose emission properties change in response to the polarity of the surrounding environment, are used for the fluorescence sensing of intracellular environments and various chemical compounds. Herein, we propose a concept called nonpolar selective emission (NPSE) for the development of a new PRL family. Unlike the conventional emission of PRLs, the NPSE luminophore can switch to a completely non-emissive state upon a slight increase in solvent polarity. The NPSE concept offers a new means of distinguishing between nonpolar and low-polarity environments. Moreover, the NPSE property is little affected by the viscosity of the surrounding medium. We demonstrate that NPSE dyes can be used as emission sensors for molecular gases. Furthermore, we discovered the potential use of NPSE dyes as a time-dependent security ink triggered by the volatilization of polar molecules.

Coerulein B: a water-soluble and water-compatible near-infrared photoredox catalyst.

The recent expansion of photoredox catalysis into chemical biology has underscored the importance of photochemistry, attracting the attention of many researchers. On the other hand, as conventional photoredox catalysts were developed for organic synthesis, there is a necessity to develop biocompatible photoredox catalysts. Here, we show a water-soluble and water-compatible near-infrared (NIR) photoredox catalyst, coerulein B (CB). CB is a water-soluble molecule with a slightly twisted molecular structure, and its anionic species (CB-) exhibits NIR absorption and emission. We demonstrated that CB works as a water-compatible photoredox catalyst in the coupling reaction of pyridine hydrochloride and aryldiazonium salt. These results indicate that CB is one of the promising candidates for photocatalysts used in biological reactions.

BN-Embedded Aromatic Hydrocarbon Synthesis via Nucleophilic Diboration Reactions.

Activation of bis(pinacolato)diboron with aromatic lithium amide promotes diboration of the proximal C-C triple bond, leading to BN-embedded aromatic compounds. In situ treatment of the initially generated spirocyclic borate intermediate with aqueous acid or organometallic reagents enables ligand installation on the endocyclic boron atom.

Nucleophile-Triggered π-Topological Transformation: A New Synthetic Approach to Near-Infrared-Emissive Rhodamines.

We describe a π-topological transformation-based synthetic method for the preparation of a new type of near-infrared (NIR)-emissive rhodamine dye called Polymethine-embedded Rhodamine Fluorophore (PeR Fluor). In contrast to conventional NIR-emissive dyes that require tedious synthetic steps and/or a high cost, linear fully π-conjugated PeR Fluor can be regioselectively prepared in one step by mixing different nucleophiles with ABPXs, a family of rhodamines with a cross-conjugated structure. PeR Fluor exhibits bright NIR fluorescence emission and high photostability owing to the cooperative π-electron system of rhodamines and polymethine scaffolds. Large bathochromic shifts of the absorption and fluorescence emission maxima can be achieved by modifying the N-substituted group to obtain NIR-absorbing/emitting PeR Fluor. We also demonstrate the stimulus-responsive functionality of PeR Fluor through the addition of chemicals (acid/base), which shows switchable NIR and visible fluorescence response. Our π-topological transformation-based synthetic method is a promising approach to produce new functionalized rhodamine dyes.

Xanthene-based functional dyes: towards new molecules operating in the near-infrared region.

Xanthene-based functional dyes have diverse applications in life science and materials science. A current challenge is to develop new dyes with suitable physicochemical properties, including near-infrared (NIR) operation, for advanced biological applications such as medical diagnostics and molecular imaging. In this review, we first present an overview of xanthene-based functional dyes and then focus on synthetic strategies for modulating the absorption and fluorescence of dyes that operate in the NIR wavelength region with bright emission and good photostability. We also introduce our work on aminobenzopyranoxanthenes (ABPXs) and bridged tetra-aryl-p-quinodimethanes (BTAQs) as new xanthene-based far-red (FR)/NIR absorbing/emitting molecules whose absorption/fluorescence wavelengths change in response to external stimuli.

Visualization of the photodegradation of a therapeutic drug by chemometric-assisted fluorescence spectroscopy.

The fluorescence spectral fingerprint, also known as the excitation-emission matrix (EEM), is used to assess and visualize therapeutic drug photodegradation in combination with chemometrics. Examination of EEM-parallel factor analysis (PARAFAC) data showed that an individual component was easily separated from a mixture of photogenerated products of a heterocyclic pharmacophore, in this case, phenothiazine drugs (PTZs). Detailed investigations of both structure-EEM relationships and kinetics revealed that the components extracted from EEM-PARAFAC could be quantitatively attributed to such photogenerated products as phenothiazine sulfoxide and carbazole derivatives. EEM in combination with principal component analysis (PCA) could be used as a mapping tool to visualize information of the photodegradation process of PTZs. We also assessed the photostability of various types of PTZs containing side chains by using validated EEM-PARAFAC methodology.

Bridged eosin Y: a visible and near-infrared photoredox catalyst.

Herein, a new NIR photoredox catalyst, bridged eosin Y (BEY), has been developed. Its detailed structure and NIR optical properties are clarified by using various spectroscopic methods, X-ray single-crystal structure analysis and DFT calculations. In addition, we demonstrate the photoreaction in colored reagents and high-concentration suspensions to show the advantage of NIR photoredox-catalyzed reactions.

cis-3-Azido-2-methoxyindolines as safe and stable precursors to overcome the instability of fleeting 3-azidoindoles.

Use of 3-azidoindoles in organic synthesis remains a difficult task owing to their instabilities. Herein, we report a general and concise approach for tackling this problem by using 3-azidoindole surrogates. The surrogates are bench-stable, presumably due to the observed intramolecular O-Nß bonding. The resultant fleeting intermediates undergo capturing in situ to afford 3-substitued indoles through formal ipso-substitution of the azide group by nucleophiles. In these investigations, we found that the fleeting 3-azidoindoles show a C3-electrophilic character for the first time.

Morpholine-Substituted Rhodamine Analogue with Multi-Configurational Switches for Optical Sensing of pH Gradient under Extreme Acidic Environments.

Superior pH-responsive molecules are required for the development of functional materials applicable to advanced molecular technologies. Despite having been widely developed, many rhodamine-based pH-responsive molecules exhibit a single configurational switch for "turn-on". Herein, we report a new type of rhodamine-based pH-responsive molecule with multi-configurational switches displaying stable two-step structural and color conversion in response to pH. This rhodamine analogue could be successfully applied to optical sensing of pH gradient under extreme acidic environments both in solution and on hydrogel through high-contrast color change. We demonstrated that this multi-responsive character enabled optical memory of different pH information.

A remarkably air-stable quinodimethane radical cation.

An ambient-stable radical cation of a Thiele's hydrocarbon derivative has been synthesized and its properties have been explored using a combined experimental and computational approach. The radical cation exhibited several intense near-infrared absorption bands and its solution-processed thin films showed high electrical conductivity at room temperature.

Development and characterization of a 68Ga-labeled A20FMDV2 peptide probe for the PET imaging of αvß6 integrin-positive pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal cancers. Since the majority of patients are diagnosed at an advanced stage, development of a detection method for PDAC at an earlier stage of disease progression is strongly desirable. Integrin αVß6 is a promising target for early PDAC detection because its expression increases during precancerous changes. The present study aimed to develop an imaging probe for positron emission tomography (PET) which targets αVß6 integrin-positive PDAC. We selected A20FMDV2 peptide, which binds specifically to αvß6 integrin, as a probe scaffold, and 68Ga as a radioisotope. A20FMDV2 peptide has not been previously labeled with 68Ga. A cysteine residue was introduced to the N-terminus of the probe at a site-specific conjugation of maleimide-NOTA (mal-NOTA) chelate. Different numbers of glycine residues were also introduced between cysteine and the A20FMDV2 sequence as a spacer in order to reduce the steric hindrance of the mal-NOTA on the binding probe to αVß6 integrin. In vitro, the competitive binding assay revealed that probes containing a 6-glycine linker ([natGa]CG6 and [natGa]Ac-CG6) showed high affinity to αVß6 integrin. Both probes could be labeled by 67/68Ga with high radiochemical yield (>50%) and purity (>98%). On biodistribution analysis, [67Ga]Ac-CG6 showed higher tumor accumulation, faster blood clearance, and lower accumulation in the surrounding organs of pancreas than did [67Ga]CG6. The αVß6 integrin-positive xenografts were clearly visualized by PET imaging with [68Ga]Ac-CG6. The intratumoral distribution of [68Ga]Ac-CG6 coincided with the αVß6 integrin-positive regions detected by immunohistochemistry. Thus, [68Ga]Ac-CG6 is a useful peptide probe for the imaging of αVß6 integrin in PDAC.

[Development of External Stimuli-responsive Organic π Molecules and the Creation of Novel Photo-functions].

We have found that the spiro form of aminobenzopyranoxanthene (ABPX) exhibits dual solvatochromic and nanoaggregate fluorescence in organic solvents by spectrophotometric and theoretical analyses. The dual fluorescence properties of ABPX were adjustable in response to water content, and served as a new detection principal for naked-eye visualization (above 0.5 wt%) and quantification (0.010-0.125 wt%) of water in tetrahydrofuran. In investigating the optical properties of a dicationic form of ABPX, ABPX containing linear n-alkyl chains at amino groups were then synthesized. These ABPX exhibited fluorescence emission in the far-red and NIR wavelength regions, and we noted an increased fluorescence quantum efficiency with increasing n-alkyl chain length. To further improve the fluorescence quantum yields, we have designed and synthesized ABPX with different nitrogen-containing fused rings. It was kinetically demonstrated that the structurally rigid conjugation of the xanthene moiety is an effective molecular design for the drastic enhancement of fluorescence emission efficiency.

Stable Thiele's Hydrocarbon Derivatives Exhibiting Near-Infrared Absorption/Emission and Two-Step Electrochromism.

We report synthesis and characterization of near-infrared (NIR)-absorbing/emitting Thiele's hydrocarbon derivatives, in which four aryl groups are bridged to a quinodimethane skeleton. The quinoid structure of the bridged-tetra-aryl- p-quinodimethanes (BTAQs) was confirmed by spectroscopic, X-ray crystallographic, and computational methods. Although quinodimethane derivatives with a small HOMO-LUMO energy gap often exhibit biradical character, BTAQs showed no biradical character. Instead, they exhibited two-step near-infrared electrochromism. The donor/acceptor properties of the aryl groups were found to play a key role in the unique properties of BTAQs.

Synthesis of Aminobenzopyranoxanthenes with Nitrogen-Containing Fused Rings.

An efficient and practical method for the synthesis of a variety of aminobenzopyranoxanthenes (ABPXs) with different nitrogen-containing fused rings was developed. On the basis of the mechanistic studies of the formation of the xanthene framework, the presented methodology was developed to facilitate access to previously inaccessible asymmetric ABPXs.

Investigation of Biodistribution and Speciation Changes of Orally Administered Dual Radiolabeled Complex, Bis(5-chloro-7-[131I]iodo-8-quinolinolato)[65Zn]zinc.

Many zinc (Zn) complexes have been developed as promising oral antidiabetic agents. In vitro assays using adipocytes have demonstrated that the coordination structures of Zn complexes affect the uptake of Zn into cells and have insulinomimetic activities, for which moderate stability of Zn complexes is vital. The complexation of Zn plays a major role improving its bioavailability. However, investigation of the speciation changes of Zn complexes after oral administration is lacking. A dual radiolabeling approach was applied in order to investigate the speciation of bis(5-chloro-7-iodo-8-quinolinolato)zinc complex [Zn(Cq)2], which exhibits the antidiabetic activity in diabetic mice. In the present study, 65Zn- and 131I-labeled [Zn(Cq)2] were synthesized, and their biodistribution were analyzed after an oral administration using both invasive conventional assays and noninvasive gamma-ray emission imaging (GREI), a novel nuclear medicine imaging modality that enables analysis of multiple radionuclides simultaneously. The GREI experiments visualized the behavior of 65Zn and [131I]Cq from the stomach to large intestine and through the small intestine; most of the administered Zn was transported together with clioquinol (5-chloro-7-iodo-8-quinolinol) (Cq). Higher accumulation of 65Zn for [Zn(Cq)2] than ZnCl2 suggests that the Zn associated with Cq was highly absorbed by the intestinal tract. In particular, the molar ratio of administered iodine to Zn decreased during the distribution processes, indicating the dissociation of most [Zn(Cq)2] complexes. In conclusion, the present study successfully evaluated the speciation changes of orally administered [Zn(Cq)2] using the dual radiolabeling method.

Water-tunable solvatochromic and nanoaggregate fluorescence: dual colour visualisation and quantification of trace water in tetrahydrofuran.

While investigating the unique optical properties of aminobenzopyranoxanthenes (ABPXs), organic fluorescent dyes with the fusion of two rhodamines, we have found that the spirolactone form of ABPXs exhibited solvatochromic fluorescence in organic solvents. Detailed spectrophotometric and theoretical analyses showed that the solvatochromic fluorescence of ABPXs originated from the photo-excited charge separation in solvents of different dipolarities. Further studies revealed that fluorescent nanoaggregates were also formed in highly concentrated solution. The intriguing dual fluorescence properties of ABPXs were tunable in response to the water content, and served as a new detection principle for naked-eye visualisation (above 0.5 wt%) and quantification (0.010-0.125 wt%) of water in tetrahydrofuran.

Fused-Fluoran Leuco Dyes with Large Color-Change Derived from Two-Step Equilibrium: iso-Aminobenzopyranoxanthenes.

Fluorans are popular leuco dyes that are used in various applications, such as carbonless-copy papers and thermal papers. Here, we describe unique leuco dyes in which two fluoran units are fused into a C2h structure (iso-aminobenzopyranoxanthenes; iso-ABPXs). iso-ABPXs exhibited a large two-step color change (colorless/pink and pink/blue-green) due to opening-closing of two spirolactone rings. The two-step equilibrium among the colorless, pink, and blue-green forms could be well controlled by adjusting acid concentration, solvent, and/or temperature.

Noninvasive evaluation of nicotinic acetylcholine receptor availability in mouse brain using single-photon emission computed tomography with [(123)I]5IA.

INTRODUCTION: Nicotinic acetylcholine receptors (nAChRs) are of great interest because they are implicated in higher brain functions. Nuclear medical imaging is one of the useful techniques for noninvasive evaluation of physiological and pathological function in living subjects. Recent progress in nuclear medical imaging modalities enables the clear visualization of the organs of small rodents. Thus, translational research using nuclear medical imaging in transgenic mice has become possible and helps to elucidate human disease pathology. However, imaging of α4ß2 nAChRs in the mouse brain has not yet been performed. The purpose of this study was to assess the feasibility of single-photon emission computed tomography (SPECT) with 5-[(123)I]iodo-3-[2(S)-azetidinylmethoxy]pyridine ([(123)I]5IA) for evaluating α4ß2 nAChR availability in the mouse brain. METHODS: A 60-min dynamic SPECT imaging session of α4ß2 nAChRs in the mouse brain was performed. The regional distribution of radioactivity in the SPECT images was compared to the density of α4ß2 nAChRs measured in an identical mouse. Alteration of nAChR density in the brains of Tg2576 mice was also evaluated. RESULTS: The mouse brain was clearly visualized by [(123)I]5IA-SPECT and probe accumulation was significantly inhibited by pretreatment with (-)-nicotine. The regional distribution of radioactivity in SPECT images showed a significant positive correlation with α4ß2 nAChR density measured in an identical mouse brain. Moreover, [(123)I]5IA-SPECT was able to detect the up-regulation of α4ß2 nAChRs in the brains of Tg2576 transgenic mice. CONCLUSIONS: [(123)I]5IA-SPECT imaging would be a promising tool for evaluating α4ß2 nAChR availability in the mouse brain and may be useful in translational research focused on nAChR-related diseases.

Enhanced stability of Cu(2+)-ATCUN complexes under physiologically relevant conditions by insertion of structurally bulky and hydrophobic amino acid residues into the ATCUN motif.

Copper complexes formed by an amino terminal Cu(2+)- and Ni(2+)-binding (ATCUN) motif have attracted attention as metallodrug candidates that cleave DNA or RNA and inactivate enzymes. Although the stability of the Cu(2+)-ATCUN complex under physiologically relevant conditions is a key factor for medical applications, it has remained unclear. Here we prepared a series of ATCUN peptides by inserting various amino acid residues into positions 1 and 2, and investigated the stability of the Cu(2+)-ATCUN complexes in aqueous solution, blood plasma, and living animals. Systematic pH titration showed that the low basicity of the N-terminal amine of the peptide stabilized the Cu(2+)-ATCUN complex in aqueous solution. Interestingly, the stability of (64)Cu-labeled ATCUN complexes in blood plasma was significantly enhanced by the structural bulkiness and hydrophobicity of the amino acid residues at positions 1 and 2. To validate the in vivo stability, six ATCUN motifs (YYH, VVH, NNH, TTH, GGH, and DDH) were conjugated to a tumor-targeting peptide, octreotide (Oct). The stability of the (64)Cu-ATCUN-Oct complexes in blood plasma showed a similar trend to that of the (64)Cu-ATCUN complexes. The (64)Cu-YYH-Oct complex exhibited the highest stability in blood plasma. According to the positron emission tomography and competitive blocking studies of a tumor-bearing mouse model, (64)Cu-YYH-Oct specifically accumulated in tumors, suggesting that the complex was sufficiently stable to reach its target in vivo. The results show that the structural bulkiness and hydrophobicity of the residues at positions 1 and 2 are key parameters for designing metallodrugs on the basis of the Cu(2+)-ATCUN complex.

Visualization of biodistribution of Zn complex with antidiabetic activity using semiconductor Compton camera GREI.

Various types of zinc (Zn) complexes have been developed as promising antidiabetic agents in recent years. However, the pharmacological action of Zn complex is not elucidated because the biodistribution of the complex in a living organism has not been studied. Nuclear medicine imaging is superior technology for the noninvasive analysis of the temporal distribution of drug candidates in living organisms. Gamma-ray emission imaging (GREI), which was developed by our laboratory as a novel molecular imaging modality, was adopted to visualize various γ-ray-emitting radionuclides that are not detected by conventional imaging techniques such as positron emission tomography and single-photon emission computed tomography. Therefore, we applied GREI to a biodistribution assay of Zn complexes. In the present study, 65Zn was produced in the natCu(p,n) reaction in an azimuthal varying field cyclotron for the GREI experiment. The distribution was then noninvasively visualized using GREI after the intravenous administration of a 65Zn-labeled di(1-oxy-2-pyridinethiolato)zinc [Zn(opt)2], ZnCl2, and di(l-histidinato)zinc. The GREI images were validated using conventional invasive assays. This novel study showed that GREI is a powerful tool for the biodistribution analysis of antidiabetic Zn complexes in a living organism. In addition, accumulation of 65Zn in the cardiac blood pool was observed for [Zn(opt)2], which exhibits potent antidiabetic activity. These results suggest that the slow elimination of Zn from the blood is correlated to the antidiabetic activity of [Zn(opt)2].