We provide the first evidence for the capability of a high-resolution positron emission tomographic (PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor ...protein transgenic (Tg) mice. After the intravenous administration of N-11Cmethyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or 11CPIB for "Pittsburgh Compound-B") with high-specific radioactivity, the Tg mice exhibited high-level retention of radioactivity in amyloid-rich regions. PET investigation for Tg mice over an extended range of ages, including longitudinal assessments, demonstrated age-dependent increase in radioligand binding consistent with progressive amyloid accumulation. Reduction in amyloid levels in the hippocampus of Tg mice was also successfully monitored by multiple PET scans along the time course of anti-amyloid treatment using an antibody against amyloid beta peptide (Abeta). Moreover, PET scans with 18Ffluoroethyl-DAA1106, a radiotracer for activated glia, were conducted for these individuals parallel to amyloid imaging, revealing treatment-induced neuroinflammatory responses, the magnitude of which intimately correlated with the levels of pre-existing amyloid estimated by 11CPIB. It is also noteworthy that the localization and abundance of 11CPIB autoradiographic signals were closely associated with those of N-terminally truncated and modified Abeta, AbetaN3-pyroglutamate, in Alzheimer's disease (AD) and Tg mouse brains, implying that the detectability of amyloid by 11CPIB positron emission tomography is dependent on the accumulation of specific Abeta subtypes. Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.
National Institutes for Quantum Science and Technology (QST), formerly known as the National Institute of Radiological Sciences (NIRS), has been engaged in work on radiopharmaceutical science using ...cyclotrons since 1974. Eight pioneering researchers founded the basis of this field of research at NIRS, and to the present, many researchers and technicians have accumulated both scientific and technical achievements, as well as inherited the spirit of research. Besides, in recent years, we have developed production systems with AVF-930 cyclotron for various ‘non-standard’ radioisotopes applied in both diagnosis and therapy. Here, we review the past 50 years of our activities on radioisotope and radiopharmaceutical development, as well as more recent activities.
The authors developed and applied two new linearized reference tissue models for parametric images of binding potential (BP) and relative delivery (R1) for 11CDASB positron emission tomography ...imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTMO) was modified (MRTM) and used to estimate a clearance rate (k′2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k′2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual 11CDASB data. MRTM gave k′2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTMO from 12–70% to 1–4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human 11CDASB positron emission tomography studies.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By ...radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like Abeta deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tau-induced massive neuronal loss was distinct from the marginal neurodegeneration associated with Abeta plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus Abeta pathologies, respectively. This notion was subsequently examined in models of various non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential PBR upregulation: (1) PBR(-) astrogliosis uncoupled with microgliosis or coupled with PBR(+) microgliosis associated with irreversible neuronal insults; and (2) PBR(+) astrogliosis coupled with PBR(- or +/-) microgliosis associated with minimal or reversible neuronal toxicity. Intracranial transplantation of microglia also indicated that nontoxic microglia drives astroglial PBR expression. Moreover, levels of glial cell line-derived neurotrophic factor (GDNF) in astrocytes were correlated with astroglial PBR, except for increased GDNF in PBR(-) astrocytes in the model of AD-like tau pathology, thereby suggesting that PBR upregulation in astrocytes is an indicator of neurotrophic support. Together, PBR expressions in astrocytes and microglia reflect beneficial and deleterious glial reactions, respectively, in diverse neurodegenerative disorders including AD, pointing to new applications of PBR imaging for monitoring the impact of gliosis on the pathogenesis and treatment of AD.
Abstract Elevated levels of peripheral benzodiazepine receptor (PBR) in glia have been documented in diverse nervous system injuries, while the identity and spatiotemporal characteristics of the ...cells showing upregulation of PBR remain elusive. We examined the astrocytic and microglial expressions of PBR in rat brains during the duration of ethanol-induced neuronal insults in order to clarify the significance of PBR as a biomarker capable of detecting a distinctive subpopulation of these glial cells involved in the impairment and protection of neurons. The levels of PBR, as determined by autoradiographic analysis using a specific radioligand, 11 CDAA1106, began to significantly increase at 3 days after intrastriatal injection of ethanol, and peaked at 7 days. This was consistent with the results of double immunofluorescence staining and high-resolution emulsion autoradiography, which revealed upregulation of PBR in both microglia and astrocytes proliferating in nonoverlapping compartments of the injury site. Notably, increased expression of PBR in astrocytes was transiently observed in a manner parallel to the centripetal migration of these cells to the inflammatory lesion, which may be a response indispensable to the protection of intact tissue. Thereafter, astrocytic PBR was barely detectable, despite the presence of numerous glial fibrillary acidic protein-immunoreactive astrocytes forming glial scarring. By contrast, intense PBR signals were persistently present in microglia localized to the injury epicenter up to 90 days, notwithstanding a gradual reduction in the number of ionized calcium binding adapter molecule-1-positive amoeboid microglia between 7 and 90 days. The long-lasting PBR expression in microglia was finally supported by in vivo positron emission tomography imaging, and suggests that inflammatory tissue damage is potentially expandable unless it is tightly sealed by astrocytic scar. The present findings collectively support the utility of PBR in identifying a unique temporal pattern of astrocytic and microglial activation that conventional glial markers hardly pursue.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Fluorine-18 ((18)F, beta(+); 96.7%, T(1/2)=109.8 min) is of considerable importance for developing positron emission tomography (PET) ligands for imaging receptor, enzyme, gene expression etc. in ...brain, tumor, myocardium and other regions or organs due to its optimal decay characteristics. To synthesize (18)F-labeled PET ligands, reliable labeling techniques inserting (18)F into a target molecule are necessary. (18)FFluoroalkylation is a useful way of introducing (18)F into target molecules containing amino, phenol, thiophenol, and amide functional groups. Here, we review the preparation, reactivity and application of (18)Ffluoroalkyl agents for the development of (18)F-labeled PET ligands in molecular imaging. (18)FFluoroalkyl agents have been synthesized by reacting (18)FF(-) with the corresponding alkyl derivatives containing halogen and sulfonate as leaving groups. After the fluorination reaction, the radiolabeled products with relatively low boiling points were distilled from the reaction mixtures, sometimes added by Sep-Pak or gas chromatography separation. The (18)Ffluoromethyl agents have high reactivity with nucleophilic substrates, but many (18)Ffluoromethylated compounds are in vitro unstable. To increase the efficiency of (18)Ffluoroethylation, (18)FFCH2CH2Br, the most frequently used (18)Ffluoroethyl agent, was converted into (18)FFCH2CH2I or (18)FFCH2CH2OTf in situ. Most (18)Ffluoromethylated ligands were found to be in vivo unstable due to defluorination. Deuterium substitution for the fluoromethyl group reduced defluorination to an extent. A number of (18)Ffluoroethylated PET ligands have been developed for animal evaluation and clinical investigation.
To develop a positron emission tomography (PET) ligand for imaging the ‘peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four ...analogues (4−7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K i = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 (18F, β+; 96.7%, T 1/2 = 109.8 min). Ligands 18F4 and 18F5 were respectively synthesized by the alkylation of desmethyl precursor 3 with 18Ffluoromethyl iodide (18F8) and 2-18Ffluoroethyl bromide (18F9). The distribution patterns of 18F4 and 18F5 in mice were consistent with the known distribution of PBR. However, compared with 18F5, 18F4 displayed a high uptake in the bone of mice. The PET image of 18F4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand 18F5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of 18F5 in monkey brain was 1.5 times higher than that of 11C2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-11Cmethyl,N-(1-methylpropyl)isoquinoline (11C1). Moreover, the in vivo binding of 18F5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of 18F5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that 18F4 was rapidly metabolized by defluorination to 18FF- in the plasma and brain of mice, whereas 18F5 was metabolized by debenzylation to a polar product 18F13 only in the plasma. No radioactive metabolite of 18F5 was detected in the mouse brain. The biological data indicate that 18F5 is a useful PET ligand for PBR and is currently used for imaging PBR in human brain.
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