Development of a Pyrone-Fused Tricyclic Scaffold-based Ratiometric Fluorescent Probe for Al Detection.

Aluminum (Al) is environmentally abundant and can harm living organisms in various ways, such as by inhibiting root growth, damaging faunal nervous systems, and promoting tumor cell proliferation. However, the dynamics of Al in living organisms are largely unknown; thus, detecting Al in the environment and organisms is crucial. Fluorescent probes are useful tools for the selective detection of metal ions.

Development of a water-soluble fluorescent Al probe based on phenylsulfonyl-2-pyrone in biological systems.

Background: Al exists naturally in the environment and is an important component in acidic soils, which harm almost all plants. Furthermore, Al is widely used in food additives, cosmetics, and medicines, resulting in living organisms ingesting traces of Al orally or dermally every day. Accordingly, Al accumulates in the body, which can cause negative bioeffects and diseases, and this concern is gaining increasing attention.

High-Affinity Ratiometric Fluorescence Probe Based on 6-Amino-2,2'-Bipyridine Scaffold for Endogenous Zn and Its Application to Living Cells.

Zinc is an essential trace element involved in many biological activities; however, its functions are not fully understood. To elucidate the role of endogenous labile Zn, we developed a novel ratiometric fluorescence probe, 5-(4-methoxyphenyl)-4-(methylsulfanyl)-[2,2'-bipyridin]-6-amine ( ()) based on the 6-amino-2,2'-bipyridine scaffold, which acts as both the chelating agent for Zn and the fluorescent moiety. The methoxy group acted as an electron donor, enabling the intramolecular charge transfer state of (), and a ratiometric fluorescence response consisting of a decrease at the emission wavelength of 438 nm and a corresponding increase at the emission wavelength of 465 nm was observed.

Development of novel radioiodinated exendin-4 derivatives targeting GLP-1 receptor for detection of β-cell mass.

In subjects with type 2 diabetes mellitus (T2DM), pancreatic β-cell mass decreases; however, it is unknown to what extent this decrease contributes to the pathophysiology of T2DM. Therefore, the development of a method for noninvasive detection of β-cell mass is underway. We previously reported that glucagon-like peptide-1 receptor (GLP-1R) is a promising target molecule for β-cell imaging.

First-in-Human Evaluation of Positron Emission Tomography/Computed Tomography With [F]FB(ePEG12)12-Exendin-4: A Phase 1 Clinical Study Targeting GLP-1 Receptor Expression Cells in Pancreas.

Pancreatic β-cell mass (BCM) has a central importance in the pathophysiology of diabetes mellitus. Recently, pancreatic β-cell-specific imaging, especially positron emission tomography (PET) with exendin-based probes, has emerged for non-invasive evaluation of BCM. We developed a novel exendin-based probe labeled with fluorine-18, [F]FB(ePEG12)12-exendin-4 (F-Ex4) for PET imaging.

Distinctive detection of insulinoma using [F]FB(ePEG12)12-exendin-4 PET/CT.

Specifying the exact localization of insulinoma remains challenging due to the lack of insulinoma-specific imaging methods. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging, especially positron emission tomography (PET), has emerged. Although various radiolabeled GLP-1R agonist exendin-4-based probes with chemical modifications for PET imaging have been investigated, an optimal candidate probe and its scanning protocol remain a necessity.

Selective Cadmium Fluorescence Probe Based on Bis-heterocyclic Molecule and its Imaging in Cells.

Fluorescence probes that selectively image cadmium are useful for detecting and tracking the amount of Cd in cells and tissues. In this study, we designed and synthesized a novel Cd fluorescence probe based on the pyridine-pyrimidine structure, 4-(methylsulfanyl)-6-(pyridin-2-yl)pyrimidin-2-amine (3), as a low-molecular-weight fluorescence probe for Cd. Compound 3 could successfully discriminate between Cd and Zn and exhibited a highly selective turn-on response toward Cd over biologically related metal ions.

Increased [F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors.

Background: [F]Fluoromisonidazole ([F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [F]FMISO uptake level varied depending on the cellular glutathione conjugation and excretion ability such as enzyme activity of glutathione-S-transferase and expression levels of multidrug resistance-associated protein 1 (MRP1, an efflux transporter), in addition to the cellular hypoxic state.

Development of Gold Nanorods Conjugated with Radiolabeled Anti-human Epidermal Growth Factor Receptor 2 (HER2) Monoclonal Antibody as Single-Photon Emission Computed Tomography/Photoacoustic Dual-Imaging Probes Targeting HER2-Positive Tumors.

Surgery remains one of the main treatments of cancer and both precise pre- and intraoperative diagnoses are crucial in order to guide the operation. We consider that using an identical probe for both pre- and intra-operative diagnoses would bridge the gap between surgical planning and image-guided resection. Therefore, in this study, we developed gold nanorods (AuNRs) conjugated with radiolabeled anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and investigated their feasibility as novel HER2-targeted dual-imaging probes for both single photon emission computed tomography (SPECT) (preoperative diagnosis) and photoacoustic (PA) imaging (intraoperative diagnosis).

Spatial Patterns of Amyloid Deposition in Patients with Chronic Focal or Diffuse Traumatic Brain Injury Using F-FPYBF-2 PET.

Aim: Amyloid-β (Aβ) accumulation, accelerated by traumatic brain injury (TBI), may play a crucial role in neurodegeneration in chronic-stage TBI. The injury type could influence Aβ dynamics because of TBI's complex, heterogeneous nature. We, therefore, investigated spatial patterns of amyloid deposition according to injury type after TBI using 5-(5-(2-(2-(2-[F]-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)--methylpyridin-2-amine (F-FPYBF-2) positron emission tomography (PET).

Sensitive Photoacoustic/Magnetic Resonance Dual Imaging Probe for Detection of Malignant Tumors.

In order to completely remove tumors in surgeries, probes are needed both preoperatively and intraoperatively. For tumor diagnosis, magnetic resonance imaging (MRI) has been widely used as a precise preoperative method, and photoacoustic imaging (PAI) is a recently emerged intraoperative (or preoperative) method, which detects ultrasonic waves thermoelastically induced by optical absorbers irradiated by laser. Iron oxide nanoparticles (IONPs) can be used as both MR and PA imaging probes.

Activatable Fluorescence Imaging of Macrophages in Cerebral Aneurysms Using Iron Oxide Nanoparticles Conjugated With Indocyanine Green.

Background And Purpose: Chronic inflammation is involved in the formation and enlargement of cerebral aneurysms (CAs), with macrophages playing a key role in the process. The present study evaluated visualization of macrophages present in CAs using an activatable fluorescent probe (IONP-ICG) comprising an iron oxide nanoparticles (IONPs) conjugated with indocyanine green (ICG).

Methods: IONP-ICG was intravenously administered to 15-week-old CA model rats ( = 8), and near-infrared fluorescence (NIRF) imaging and histological assessment of exposed CAs and cerebral arteries were performed 48 h later.

Development and characterization of a Ga-labeled A20FMDV2 peptide probe for the PET imaging of αvβ6 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 αβ6 is a promising target for early PDAC detection because its expression increases during precancerous changes.

Evaluation of [F]pitavastatin as a positron emission tomography tracer for in vivo organic transporter polypeptide function.

Introduction: To understand the pathways involved in drug clearance from the body, quantitative evaluations of the hepatobiliary transport of drugs are important. The organic anion transporting polypeptide (OATP) family transporter, particularly OATP1B1 and 1B3, are considered to play an important role in hepatic uptake of organic anion compounds. Pitavastatin is a substrate of OATP, and it includes a fluorine group.

Development of Tc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand Tc-A-YN-IDA-C4.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (Tc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography.

Noninvasive longitudinal quantification of β-cell mass with [In]-labeled exendin-4.

Currently, quantifying β-cell mass (BCM) requires harvesting the pancreas. In this study, we investigated a potential noninvasive method to quantify BCM changes longitudinally using [Lys(In-BnDTPA-Ahx)]exendin-4 ([In]-Ex4) and single-photon emission computed tomography (SPECT). We used autoradiography and transgenic mice expressing green fluorescent protein under the control of mouse insulin 1 gene promotor to evaluate the specificity of [In]-Ex4 toward β cells.

Evaluation of transporter-mediated hepatobiliary transport of newly developed F-labeled pitavastatin derivative, PTV-F1, in rats by PET imaging.

Quantitative evaluations of the functions of uptake and efflux transporters directly in vivo is desired to understand an efficient hepatobiliary transport of substrate drugs. Pitavastatin is a substrate of organic anion transporting polypeptides (OATPs) and canalicular efflux transporters; thus, it can be a suitable probe for positron-emission tomography (PET) imaging of hepatic transporter functions. To characterize the performance of [F]PTV-F1, an analogue of pitavastatin, we investigated the impact of rifampicin (a typical OATP inhibitor) coadministration or Bcrp (breast cancer resistance protein) knockout on [F]PTV-F1 hepatic uptake and efflux in rats by PET imaging.

F-labeled benzimidazopyridine derivatives for PET imaging of tau pathology in Alzheimer's disease.

Hyperphosphorylated tau proteins are one of the neuropathological hallmarks in the Alzheimer's disease (AD) brain. The in vivo imaging of tau aggregates with nuclear medical imaging probes is helpful for the further comprehension of and medical intervention in the AD pathology. For tau-selective PET imaging, we newly designed and synthesized F-labeled benzimidazopyridine (BIP) derivatives with fluoroalkylamino groups, [F]IBIPF1 and [F]IBIPF2, and evaluated their utilities as tau imaging probes.

Development of Technetium-99m-Labeled BODIPY-Based Probes Targeting Lipid Droplets Toward the Diagnosis of Hyperlipidemia-Related Diseases.

Hyperlipidemia causes systemic lipid disorder, which leads to hepatic steatosis and atherosclerosis. Thus, it is necessary to detect these syndromes early and precisely to improve prognosis. In the affected regions, abnormal formation and growth of lipid droplets is observed; therefore, lipid droplets may be a suitable target for the diagnosis of hyperlipidemia-related syndromes.

Synthesis and biological evaluation of F-18 labeled tetrahydroisoquinoline derivatives targeting orexin 1 receptor.

Orexin 1 receptor (OXR) is thought to be involved in various body functions, including arousal maintenance and emotional control, but the full details of its function remain unknown. OXR imaging with positron emission tomography (PET) would be useful in elucidating the orexin system including OXR, but no PET probes targeting OXR have been reported. We, therefore, designed and synthesized tetrahydroisoquinoline (THIQ) derivatives as novel PET probes targeting OXR, and evaluated their utility.

Synthesis of a Novel Pyrazine⁻Pyridone Biheteroaryl-Based Fluorescence Sensor and Detection of Endogenous Labile Zinc Ions in Lung Cancer Cells.

A small extent of endogenous labile zinc is involved in many vital physiological roles in living systems. However, its detailed functions have not been fully elucidated. In this study, we developed a novel biheteroaryl-based low molecular weight fluorescent sensor, 3-(phenylsulfonyl)-pyrazine-pyridone (), and applied it for the detection of endogenous labile zinc ions from lung cancer cells during apoptosis.

Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380: An imaging probe for single-photon emission computed tomography investigation of nicotinic acetylcholine receptors in the brain.

We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([Tc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (Tc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated.

Development of the Tc-Hydroxamamide Complex as a Probe Targeting Carbonic Anhydrase IX.

Carbonic anhydrase IX (CA-IX) is regarded as a favorable target for in vivo imaging because of its specific expression in hypoxic regions of tumors. Hypoxia assists tumor propagation and growth and is resistant to chemotherapy and radiotherapy. Here, we designed and synthesized [Tc]hydroxamamide ([Tc]Ham) and [Tc]methyl-substituted-hydroxamamide ([Tc]MHam) complexes including a bivalent CA-IX ligand, sulfonamide (SA), and ureidosulfonamide (UR).

Initial evaluation of PET/CT with F-FSU-880 targeting prostate-specific membrane antigen in prostate cancer patients.

This first-in-man study was carried out to evaluate the safety, whole-body distribution, dose estimation, and lesion accumulation of F-FSU-880, a newly developed probe targeting prostate-specific membrane antigen. Six prostate cancer patients with known metastatic lesions underwent serial whole-body PET/computed tomography (CT) with F-FSU-880. Blood and urine were analyzed before and after PET/CT.