Yoichi Ishikawa

18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease

Imaging of neurofibrillary pathology in the brain helps in diagnosing dementia, tracking disease progression, and evaluating the therapeutic efficacy of antidementia drugs. The radiotracers used in this imaging must be highly sensitive and specific for tau protein fibrils in the human brain. We developed a novel tau PET tracer, 18F-THK5351, through compound optimization of arylquinoline derivatives. Methods: The in vitro binding properties, pharmacokinetics, and safety of 18F-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed. Results: 18F-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white-matter tissue than did 18F-THK5117. The THK5351 binding amount correlated with the amount of tau deposits in human brain samples. Autoradiography of brain sections revealed that THK5351 bound to neurofibrillary tangles selectively and with a higher signal-to-background ratio than did THK5117. THK5351 exhibited favorable pharmacokinetics and no defluorination in mice. In first-in-human PET studies in AD patients, 18F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than18F-THK5117. Conclusion: 18F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.

Longitudinal Assessment of Tau Pathology in Patients with Alzheimer’s Disease Using [18F]THK-5117 Positron Emission Tomography

The formation of neurofibrillary tangles is believed to contribute to the neurodegeneration observed in Alzheimer’s disease (AD). Postmortem studies have shown strong associations between the neurofibrillary pathology and both neuronal loss and the severity of cognitive impairment. However, the temporal changes in the neurofibrillary pathology and its association with the progression of the disease are not well understood. Tau positron emission tomography (PET) imaging is expected to be useful for the longitudinal assessment of neurofibrillary pathology in the living brain. Here, we performed a longitudinal PET study using the tau-selective PET tracer [18F]THK-5117 in patients with AD and in healthy control subjects. Annual changes in [18F]THK-5117 binding were significantly elevated in the middle and inferior temporal gyri and in the fusiform gyrus of patients with AD. Compared to patients with mild AD, patients with moderate AD showed greater changes in the tau load that were more widely distributed across the cortical regions. Furthermore, a significant correlation was observed between the annual changes in cognitive decline and regional [18F]THK-5117 binding. These results suggest that the cognitive decline observed in patients with AD is attributable to the progression of neurofibrillary pathology. Longitudinal assessment of tau pathology will contribute to the assessment of disease progression and treatment efficacy.

Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin

The strength of sedation due to antihistamines can be evaluated using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy following oral administration of cetirizine (10 and 20 mg) in order to examine dose dependency.

Electrochemical concentration of no-carrier-added [18F]fluoride from [18O]water in a disposable microfluidic cell for radiosynthesis of 18F-labeled radiopharmaceuticals

The realization of the electrochemical method for microfluidic radiosynthesis is described for concentrating aqueous no-carrier-added [(18)F]fluoride into an aprotic solvent in a disposable microfluidic cell. Flowing aqueous [(18)F]fluoride was introduced into a disposable microfluidic cell (16microL) under an electric potential (10V), followed by anhydrous MeCN. The trapped [(18)F]fluoride was released in MeCN containing Kryptofix 222-KHCO(3) (ca. 60microL) under heat and a reversed potential (-2.5V). An automated module provided the [(18)F]fluoride ready for subsequent microfluidic radiosynthesis in overall radiochemical yields of 60% within 6min.

Initial evaluation of dynamic human imaging using18F-FRP170 as a new PET tracer for imaging hypoxia

Abstract18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxia imaging agent for positron emission tomography. This compound was synthesized by18F-labeling of RP170, which was developed as a new hydrophilic 2-nitroimidazole analog. In the present study, we analyzed dynamic whole-body imaging in healthy volunteers and dynamic tumor imaging in three patients with lung cancer.Methods: Four healthy male volunteers and three lung cancer patients were enrolled in this study. Volunteers underwent dynamic whole-body scans just after injection of18F-FRP170 for about 90 min, while the lung cancer patients underwent dynamic tumor imaging for about 60 or 120 min. Data are expressed as standardized uptake values (SUV). Regions of interest were placed over images of each organ or tumor to generate time-SUV curves.Results: The series of dynamic whole-body scans showed rapid elimination of18F-FRP170 from the kidneys following elimination from the liver. Very low physiological uptake was observed above the diaphragm.18F-FRP170 uptake in the lung cancer lesion could be visualized clearly from early after injection. The changes of tumor SUV, tumor/blood ratio, or tumor/muscle ratio about 30 min after injection or later were small.Conclusions: Dynamic imaging using18F-FRP170 demonstrated rapid elimination from the kidney, suggesting the high hydrophilicity of this imaging agent. The background activity above the diaphragm was very low, and patients with lung cancer showed clear tumor uptake of18F-FRP170 early after injection.

Reactivity of electrochemically concentrated anhydrous [18F]fluoride for microfluidic radiosynthesis of 18F-labeled compounds

In order to demonstrate the usefulness of electrochemically concentrated [(18)F]fluoride the reactivity of the [K(+)/K.222] (18)F(-) complex concentrated in an aprotic solvent (ca. 60μL) was evaluated via nucleophilic (18)F-substitution reactions through radiosynthesis of [(18)F]FDG, [(18)F]FMISO, [(18)F]flumazenil and [(18)F]fluoromethyl bromide. The substitutions were carried out in a microfluidic reaction flow cell and the effects of reaction time, temperature, precursor concentration and reaction solvent on the (18)F-substitution yields were investigated. The (18)F-fluorination yields for the four (18)F-labeled compounds under optimized conditions (98% for protected [(18)F]FDG, 80% for protected [(18)F]FMISO, 20% for [(18)F]flumazenil and 60% for [(18)F]fluoromethyl bromide) were comparable to or higher than those obtained by conventional means. In this study it is clearly demonstrated that electrochemically concentrated [(18)F]fluoride enables microfluidic radiosynthesis by effectively reducing synthesis times and especially by increasing radiochemical yields of products labile at high temperatures.

29Si and 30Si enrichment by IR MPD of Si2F6

Abstract The infrared multiple-photon decomposition of Si2F6 has been studied as a function of irradiation wavenumber using a collimated pulsed beam from a CO2 TEA laser. The main decomposition product SiF4 was found to be enriched with 29Si and 30Si. For example, SiF4 contained 6% 29Si and 46% 30Si in the irradiation of 2 Torr natural Si2F6 with the laser radiation at 949.43 cm−1 and 0.36 J cm−2.

Synthesis and preliminary evaluation of 2-arylhydroxyquinoline derivatives for tau imaging

Alzheimers disease (AD) is the most common cause of dementia. Senile plaques, consisting of β-amyloid, and neurofibrillary tangles (NFTs), composed of tau protein, are representative pathological hallmarks of AD. It is believed that the accumulation of NFTs precedes the onset of clinical symptoms of AD and correlates with the progression of memory dysfunction. Thus, the use of noninvasive detection techniques including radiolabeled probes and positron emission tomography (PET) will facilitate early diagnosis or staging of AD. In this study, we synthesized and evaluated novel hydroxylated 2-arylquinoline derivatives as tau imaging PET probes. The binding affinities of compounds for tau were evaluated by fluorescent staining of the AD hippocampal section and a competitive binding assay using [(18) F]THK-523. THK-951 showed high binding affinity for tau pathology in an AD brain section and K18Δ280K fibrils (Ki  = 20.7 nM); thus, we radiosynthesized a (11) C-labeled THK-951 and further studied its potential as a tau PET probe. The [(11) C]THK-951 demonstrated excellent kinetics in a normal mouse brain (3.23% ID/g at 2 min postinjection and 0.15% ID/g at 30 min postinjection) and showed the labeling of NFTs in an AD brain section by autoradiography assay. These findings indicate the availability of [(11) C]THK-951 for in vivo PET imaging of tau pathology in AD.

Glycemic Variability Is an Independent Predictive Factor for Development of Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease

Patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) often have metabolic disorders including insulin resistance and type 2 diabetes mellitus (T2DM). We clarified the predictive factors in glucose metabolism for progression of hepatic fibrosis in patients with NAFLD by the 75-g oral glucose tolerance test (75gOGTT) and a continuous glucose monitoring system (CGMS). One hundred sixty-nine patients (68 female and 101 male patients) with biopsy-proven NAFLD with performance with 75gOGTT were enrolled and divided into four groups according to the stage of hepatic fibrosis (F0–3). The proportion of patients with T2DM significantly gradually increased, HbA1c and the homeostasis model assessment of insulin resistance were significantly elevated, and 1,5-anhydroglucitol (1,5-AG) was remarkably decreased with the progression of fibrosis. In the 75gOGTT, both plasma glucose and insulin secretion were remarkably increased with the progression of fibrosis. The only factor significantly associated with advanced fibrosis was 1,5-AG (P = 0.008) as determined by multivariate logistic regression analysis. We next evaluated the changes in blood glucose during 24 hours by monitoring with the CGMS to confirm the relationship between glycemic variability and progression of fibrosis. Variability of median glucose, standard deviation of median glucose (P = 0.0022), maximum blood glucose (P = 0.0019), and ΔMin–max blood glucose (P = 0.0029) were remarkably higher in severe fibrosis than in mild fibrosis. Conclusion Hyperinsulinemia and hyperglycemia, especially glycemic variability, are important predictive factors in glucose impairment for the progression of hepatic fibrosis in NAFLD.

Structure–Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease

Abnormal deposition of amyloid-β and hyperphosphorylated tau protein in the brain are the pathologic hallmark of Alzheimer disease (AD). Noninvasive detection of the lesions is considered an effective tool for early diagnosis and staging of AD. In the past decade, we developed 2-arylquinoline (2-AQ) derivatives as PET tau tracers. In this study, we synthesized new derivatives and evaluated their properties. Methods: Fifteen 2-AQ derivatives were labeled with 18F, and their binding to tau lesions was evaluated by autoradiography using AD brain sections. The binding affinity for the AD brain homogenates was assessed by an in vitro competitive binding assay with 18F-THK-5105. 18F-labeled derivatives were injected into mice via the tail vein, and their pharmacokinetics over the first 120 min after injection were evaluated by an ex vivo biodistribution study. Tracer metabolism analysis was also assessed in mice. Results: The average log P value was 2.80. This study revealed that 2-AQ derivatives having 18F-labeled side chains on benzene or position 7 of the quinoline showed significantly lower binding affinity for tau than 6-substituted quinoline derivatives. The 2-AQ derivatives labeled with 18F-fluoroethoxy, 18F-fluoropropoxy, and 18F-fluoro-polyethyleneglycol groups displayed slow clearance from blood or a high accumulation in bone, whereas derivatives labeled with the 18F-(3-fluoro-2-hydroxy)propoxyl group did not. 18F-THK-5151 had outstanding tau binding properties and pharmacokinetics. Furthermore, the properties of its optically pure (S)-enantiomer (THK-5351) were superior to those of the (R)-enantiomer (THK-5451), particularly in terms of its clearance from the brain and its resistance to defluorination in mice. Conclusion: The structure–activity relationship study of 2-AQ derivatives revealed the optimal structural features for tau imaging agents. On the basis of these results, 18F-THK-5351 ((S)-18F-THK-5151) was selected as a potential agent for tau imaging.