Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-ß is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Preclinical Evaluation of a Companion Diagnostic Radiopharmaceutical, [18F]PSMA-1007, in a Subcutaneous Prostate Cancer Xenograft Mouse Model.

Several radiolabeled prostate-specific membrane antigen (PSMA)-targeted agents have been developed for detecting prostate cancer, using positron emission tomography imaging and targeted radionuclide therapy. Among them, [18F]PSMA-1007 has several advantages, including a comparatively long half-life, delayed renal excretion, and compatible structure with α-/ß-particle emitter-labeled therapeutics. This study aimed to characterize the preclinical pharmacokinetics and internal radiation dosimetry of [18F]PSMA-1007, as well as its repeatability and specificity for target binding using prostate tumor-bearing mice. In PSMA-positive tumor-bearing mice, the kidney showed the greatest accumulation of [18F]PSMA-1007. The distribution in the tumor attained its peak concentration of 2.8%ID/g at 112 min after intravenous injection. The absorbed doses in the tumor and salivary glands were 0.079 ± 0.010 Gy/MBq and 0.036 ± 0.006 Gy/MBq, respectively. The variance of the net influx (Ki) of [18F]PSMA-1007 to the tumor was minimal between scans performed in the same animals (within-subject coefficient of variation = 7.57%). [18F]PSMA-1007 uptake in the tumor was specifically decreased by 32% in Ki after treatment with a PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In the present study, we investigated the in vivo preclinical characteristics of [18F]PSMA-1007. Our data from [18F]PSMA-1007 PET/computed tomography (CT) studies in a subcutaneous prostate cancer xenograft mouse model supports clinical therapeutic strategies that use paired therapeutic radiopharmaceuticals (such as [177Lu]Lu-PSMA-617), especially strategies with a quantitative radiation dose estimate for target lesions while minimizing radiation-induced toxicity to off-target tissues.

Direct 18F-Fluorosulfurylation of Phenols and Amines Using an [18F]FSO2+ Transfer Agent Generated In Situ.

We report the direct radiofluorosulfurylation method for the synthesis of 18F-labeled fluorosulfuryl derivatives from phenols and amines using an [18F]FSO2+ transfer agent generated in situ. Nucleophilic radiofluorination is achieved even in a hydrous organic medium, obviating the need for azeotropic drying and the use of cryptands. This unprecedented, operationally simple isotopic functionalization facilitates the reliable production of potential radiotracers for positron emission tomography, rendering facile access to SuFEx radiochemistry.

Re-evaluation of the diagnostic performance of 11C-methionine PET/CT according to the 2016 WHO classification of cerebral gliomas.

PURPOSE: We evaluated the usefulness of 11C-methionine (MET) positron emission tomography/computed tomography (PET/CT) for grading cerebral gliomas according to the 2016 WHO classification with special emphasis on the presence of the isocitrate dehydrogenase 1 (IDH1) gene mutation and 1p/19q codeletion. METHODS: In total, 144 patients underwent MET PET/CT before surgery. The ratios of the maximum standardized uptake value (SUV) of the gliomas to the mean SUV of the contralateral cortex on MET PET/CT (MET TNR) were calculated. RESULTS: The median MET TNRs in IDH1-mutant and IDH1-wildtype tumours were 1.95 and 3.35, respectively. From among 74 IDH1-mutant tumours, the oligodendrogliomas showed a higher median MET TNR than the astrocytic tumours (2.90 vs. 1.40, P < 0.001). In grade II, III and IV IDH1-mutant astrocytic tumours, the median MET TNRs were 1.20, 2.05 and 2.20, respectively (grade II vs. grade III, P < 0.0001; grade II vs. grade IV, P = 0.023). In oligodendrogliomas, the MET TNR was lower fin grade II tumours than in grade III tumours (2.30 vs. 3.30 P = 0.008). In differentiating low-grade (grade II) from high-grade (grade III and IV) gliomas, receiver operating characteristic analysis showed a higher area under the curve for wildtype tumours (0.976) than for all tumours (0.852; P < 0.001) and IDH1-mutant tumours (0.817; P = 0.004). CONCLUSION: IDH1-mutant tumours showed lower MET uptake than IDH1-wildtype tumours. Regardless of IDH1 mutation status, oligodendrogliomas with 1p/19q codeletion showed MET uptake as high as that in high-grade IDH1-wildtype tumours. Therefore, MET uptake for glioma grading was more consistent for IDH1-wildtype tumours than for IDH1-mutant tumours.

Chemoselective Radiosyntheses of Electron-Rich [18F]Fluoroarenes from Aryl(2,4,6-trimethoxyphenyl)iodonium Tosylates.

Hypervalent diaryliodonium salts have been used to produce various [18F]fluoroarenes. The iodonium salt approach as a labeling precursor has been established to equally afford complex 18F-fluorinated molecules. Because of the inherent two aryl ring system connected to a central iodine atom, safeguarding the chemoselectivity during radiofluorination using diaryliodonium salts is important. Herein, we introduce a superior chemoselective radiosynthesis of [18F]fluoroarenes using an aryl(2,4,6-trimethoxyphenyl)iodonium tosylate as a precursor for 18F-incorporation, even on electron-rich aryl rings.

Automated cGMP-compliant radiosynthesis of [18 F]-(E)-PSS232 for brain PET imaging of metabotropic glutamate receptor subtype 5.

(E)-3-(Pyridin-2-yl ethynyl)cyclohex-2-enone O-(3-(2-[18 F]-fluoroethoxy)propyl) oxime ([18 F]-(E)-PSS232, [18 F]2a) is a recently developed radiotracer that can be used to visualize metabotropic glutamate receptor subtype 5 (mGlu5 ) in vivo. The mGlu5 has become an attractive therapeutic and diagnostic target owing to its role in many neuropsychiatric disorders. Several carbon-11-labeled and fluorine-18-labeled radiotracers have been developed to measure mGlu5 receptor occupancy in the human brain. The radiotracer [18 F]2a, which is used as an analogue for [11 C]ABP688 ([11 C]1) and has a longer physical half-life, is a selective radiotracer that exhibits high binding affinity for mGlu5 . Herein, we report the fully automated radiosynthesis of [18 F]2a using a commercial GE TRACERlab™ FX-FN synthesizer for routine production and distribution to nearby satellite clinics. Nucleophilic substitution of the corresponding mesylate precursor with cyclotron-produced [18 F]fluoride ion at 100°C in dimethyl sulfoxide (DMSO), followed by high-performance liquid chromatography (HPLC) purification and formulation, readily provided [18 F]2a with a radiochemical yield of 40 ± 2% (decay corrected, n = 5) at the end of synthesis. Radiochemical purity for the [18 F]-(E)-conformer was greater than 95%. Molar activity was determined to be 63.6 ± 9.6 GBq/µmol (n = 5), and the overall synthesis time was 70 minutes.

Crystal Structures of Diaryliodonium Fluorides and Their Implications for Fluorination Mechanisms.

The radiofluorination of diaryliodonium salts is of value for producing radiotracers for positron emission tomography. We report crystal structures for two diaryliodonium fluorides. Whereas diphenyliodonium fluoride (1 a) exists as a tetramer bridged by four fluoride ions, 2-methylphenyl(phenyl)iodonium fluoride (2 a) forms a fluoride-bridged dimer that is further halogen bonded to two other monomers. We discuss the topological relationships between the two and their implications for fluorination in solution. Both radiofluorination and NMR spectroscopy show that thermolysis of 2 a gives 2-fluorotoluene and fluorobenzene in a 2 to 1 ratio that is in good agreement with the ratio observed from the radiofluorination of 2-methylphenyl(phenyl)iodonium chloride (2 b). The constancy of the product ratio affirms that the fluorinations occur via the same two rapidly interconverting transition states whose energy difference dictates chemoselectivity. From quantum chemical studies with density functional theory we attribute the "ortho-effect" to the favorable electrostatic interaction between the incoming fluoride and the o-methyl in the transition state. By utilizing the crystal structures of 1 a and 2 a, the mechanisms of fluoroarene formation from diaryliodonium fluorides in their monomeric, homodimeric, heterodimeric, and tetrameric states were also investigated. We propose that oligomerization energy dictates whether the fluorination occurs through a monomeric or an oligomeric pathway.

11 C-Acetate PET/CT for Reactive Astrogliosis Outperforms 11 C-Methionine PET/CT in Glioma Classification and Survival Prediction.

PURPOSE: 11 C-acetate (ACE) PET/CT visualizes reactive astrogliosis in tumor microenvironment. This study compared 11 C-ACE and 11 C-methionine (MET) PET/CT for glioma classification and predicting patient survival. PATIENTS AND METHODS: In this prospective study, a total of 142 patients with cerebral gliomas underwent preoperative MRI, 11 C-MET PET/CT, and 11 C-ACE PET/CT. Tumor-to-contralateral cortex (TNR MET ) and tumor-to-choroid plexus ratios (TNR ACE ) were calculated for 11 C-MET and 11 C-ACE. The Kruskal-Wallis test and Bonferroni post hoc analysis were used to compare the differences in 11 C-TNR MET and 11 C-TNR ACE . The Cox proportional hazards regression analysis and classification and regression tree models were used to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The median 11 C-TNR MET and 11 C-TNR ACE for oligodendrogliomas (ODs), IDH1 -mutant astrocytomas, IDH1 -wildtype astrocytomas, and glioblastomas were 2.75, 1.40, 2.30, and 3.70, respectively, and 1.40, 1.20, 1.77, and 2.87, respectively. The median 11 C-TNR MET was significantly different among the groups, except between ODs and IDH1 -wildtype astrocytomas, whereas the median 11 C-TNR ACE was significantly different among all groups. The classification and regression tree model identified 4 risk groups ( IDH1 -mutant with 11 C-TNR ACE ≤ 1.4, IDH1 -mutant with 11 C-TNR ACE > 1.4, IDH1 -wildtype with 11 C-TNR ACE ≤ 1.8, and IDH1 -wildtype with 11 C-TNR ACE > 1.8), with median PFS of 52.7, 44.5, 25.9, and 8.9 months, respectively. Using a 11 C-TNR ACE cutoff of 1.4 for IDH1 -mutant gliomas and a 11 C-TNR ACE cutoff of 2.0 for IDH1 -wildtype gliomas, all gliomas were divided into 4 groups with median OS of 52.7, 46.8, 27.6, and 12.0 months, respectively. Significant differences in PFS and OS were observed among the 4 groups after correcting for multiple comparisons. CONCLUSIONS: 11 C-ACE PET/CT is better for glioma classification and survival prediction than 11 C-MET PET/CT, highlighting its potential role in cerebral glioma patients.

Association of Basal Forebrain Volume with Amyloid, Tau, and Cognition in Alzheimer's Disease.

Background: Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer's disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective: To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods: In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aß]-negative cognitively unimpaired, 6 Aß-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18F-florbetaben PET for Aß, 18F-flortaucipir PET for tau, and detailed cognitive testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aß and tau standardized uptake value ratio and cognition. Results: Cross-sectionally, lower BF volume was not independently associated with higher cortical Aß, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aß accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aß and tau burden. Conclusions: Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function.

Iterative SuFEx approach for sequence-regulated oligosulfates and its extension to periodic copolymers.

The synthesis of sequence-regulated oligosulfates has not yet been established due to the difficulties in precise reactivity control. In this work, we report an example of a multi-directional divergent iterative method to furnish oligosulfates based on a chain homologation approach, in which the fluorosulfate unit is regenerated. The oligosulfate sequences are determined by high resolution mass spectrometry of the hydrolyzed fragments, and polysulfate periodic copolymers are synthesized by using oligomeric bisfluorosulfates in a bi-directional fashion. The synthetic utility of this iterative ligation is demonstrated by preparing crosslinked network polymers as synthetic adhesive materials.

Single-step syntheses of no-carrier-added functionalized [18F]fluoroarenes as labeling synthons from diaryliodonium salts.

Radiotracers labelled with short-lived fluorine-18 (t(1/2) = 109.7 min) are keenly sought for biomedical imaging with positron emission tomography (PET). The radiotracers are mostly required at high specific radioactivities, necessitating their radiosyntheses from cyclotron-produced no-carrier-added [(18)F]fluoride ion. PET radiotracers encompass wide structural diversity and molecular weight. Hence, diverse (18)F-labeling methodology is needed to accomplish the required radiosyntheses in a simple and rapid manner. A useful strategy is to introduce nucleophilic [(18)F]fluoride ion first into a labeling synthon that may then be applied to label the target radiotracer. Here, we show that various functionalized [(18)F]fluoroarenes may be rapidly synthesized as labeling synthons through single-step reactions of appropriate diaryliodonium salts with [(18)F]fluoride ion. Decay-corrected radiochemical yields (RCYs) varied with position of functional group, choice of electron-rich aryl ring in the diaryliodonium salt, and choice of anion. Under best conditions, (18)F-labeled fluorobenzaldehydes, fluorobenzyl halides, fluorobenzoic acid esters and fluorophenyl ketones were obtained selectively in 40-73%, 20-55%, 46-89% and 81-98% RCYs, respectively. This versatile straightforward methodology will enhance the scope for producing structurally complex, yet useful, PET radiotracers.

Radiofluorination of diaryliodonium tosylates under aqueous-organic and cryptand-free conditions.

Positron emission tomography (PET) has growing importance as a molecular imaging technique in clinical research and drug development. Methods for producing PET radiotracers utilizing cyclotron-produced [(18)F]fluoride ion (t1/2 = 109.7 min) without the need for complete removal of irradiated target [(18)O]water and addition of cryptand are keenly sought for practical convenience and efficiency. Several structurally diverse diaryliodonium tosylates, XArI(+)Ar'Y TsO(-) (X = H or p-MeO), were investigated in a microfluidic apparatus for their reactivity towards radiofluorination with high specific activity (no-carrier-added) [(18)F]fluoride ion in mixtures of DMF and irradiated target [(18)O]water in the absence of cryptand. Salts bearing a para or ortho electron-withdrawing group Y (e.g., Y = p-CN) reacted rapidly (∼3 min) to give the expected major [(18)F]fluoroarene product, [(18)F]FArY, in useful moderate radiochemical yields even when the solvent had an [(18)O]water content up to 28%. Salts bearing electron-withdrawing groups in meta position (e.g., Y = m-NO2), or an electron-donating substituent (Y = p-OMe), gave low radiochemical yields under the same conditions.

Association of Sleep Disturbances With Brain Amyloid and Tau Burden, Cortical Atrophy, and Cognitive Dysfunction Across the AD Continuum.

BACKGROUND AND OBJECTIVES: Patients with Alzheimer disease (AD) frequently suffer from various sleep disturbances. However, how sleep disturbance is associated with AD and its progression remains poorly investigated. We investigated the association of total sleep time with brain amyloid and tau burden, cortical atrophy, cognitive dysfunction, and their longitudinal changes in the AD spectrum. METHODS: In this retrospective cohort study, we enrolled participants on the AD spectrum who were positive on 18F-florbetaben (FBB) PET. All participants underwent the Pittsburgh Sleep Quality Index, brain MRI, FBB PET, 18F-flortaucipir (FTP) PET, and detailed neuropsychological testing. In addition, a subset of participants completed follow-up assessments. We analyzed the association of total sleep time with the baseline and longitudinal FBB-standardized uptake value ratio (SUVR), FTP-SUVR, cortical thickness, and cognitive domain composite scores. RESULTS: We examined 138 participants on the AD spectrum (15 with preclinical AD, 62 with prodromal AD, and 61 with AD dementia; mean age 73.4 ± 8.0 years; female 58.7%). Total sleep time was longer in the AD dementia group (7.4 ± 1.6 hours) compared with the preclinical (6.5 ± 1.4 hours; p = 0.026) and prodromal groups (6.6 ± 1.4 hours; p = 0.001), whereas other sleep parameters did not differ between groups. Longer total sleep time was not associated with amyloid accumulation but rather with tau accumulation, especially in the amygdala, hippocampus, basal forebrain, insular, cingulate, occipital, inferior temporal cortices, and precuneus. Longer total sleep time predicted faster tau accumulation in Braak regions V-VI (ß = 0.016, p = 0.007) and disease progression to mild cognitive impairment or dementia (hazard ratio = 1.554, p = 0.024). Longer total sleep time was also associated with memory deficit (ß = -0.19, p = 0.008). DISCUSSION: Prolonged total sleep time was associated with tau accumulation in sleep-related cortical and subcortical areas as well as memory dysfunction. It also predicted faster disease progression with tau accumulation. Our study highlights the clinical importance of assessing total sleep time as a marker for disease severity and prognosis in the AD spectrum.

Visualizing Cancer-Originating Acetate Uptake Through MCT1 in Reactive Astrocytes in the Glioblastoma Tumor Microenvironment.

BACKGROUND: Reactive astrogliosis is a hallmark of various brain pathologies, including neurodegenerative diseases and glioblastomas. However, the specific intermediate metabolites contributing to reactive astrogliosis remain unknown. This study investigated how glioblastomas induce reactive astrogliosis in the neighboring microenvironment and explores 11C-acetate PET as an imaging technique for detecting reactive astrogliosis. METHODS: Through in vitro, mouse models, and human tissue experiments, we examined the association between elevated 11C-acetate uptake and reactive astrogliosis in gliomas. We explored acetate from glioblastoma cells, which triggers reactive astrogliosis in neighboring astrocytes by upregulating MAO-B and MCT1 expression. We evaluated the presence of cancer stem cells in the reactive astrogliosis region of glioblastomas and assessed the correlation between the volume of 11C-acetate uptake beyond MRI and prognosis. RESULTS: Elevated 11C-acetate uptake is associated with reactive astrogliosis and astrocytic MCT1 in the periphery of glioblastomas in human tissues and mouse models. Glioblastoma cells exhibit increased acetate production as a result of glucose metabolism, with subsequent secretion of acetate. Acetate derived from glioblastoma cells induces reactive astrogliosis in neighboring astrocytes by increasing the expression of MAO-B and MCT1. We found cancer stem cells within the reactive astrogliosis at the tumor periphery. Consequently, a larger volume of 11C-acetate uptake beyond contrast-enhanced MRI was associated with worse prognosis. CONCLUSION: Our results highlight the role of acetate derived from glioblastoma cells in inducing reactive astrogliosis and underscore the potential value of 11C-acetate PET as an imaging technique for detecting reactive astrogliosis, offering important implications for the diagnosis and treatment of glioblastomas.

Regiospecific syntheses of functionalized diaryliodonium tosylates via [hydroxy(tosyloxy)iodo]arenes generated in situ from (diacetoxyiodo)arenes.

Ready access to (18)F-labeled aryl synthons is required for preparing novel radiotracers for molecular imaging with positron emission tomography. Diaryliodonium salts react with cyclotron-produced no-carrier-added [(18)F]fluoride ion to produce [(18)F]aryl fluorides. We aimed to prepare functionalized diaryliodonium salts to serve as potential precursors for producing useful (18)F-labeled aryl synthons, such as (18)F-labeled halomethylbenzenes, benzaldehydes, and benzoic acid esters. Such salts were designed to have one functionalized aryl ring, one relatively electron-rich ring, such as 4-methoxyphenyl or 2-thienyl, and a nonfluorine containing weakly nucleophilic anion. Generation of a [hydroxy(tosyloxy)iodo]arene from a functionalized (diacetoxyiodo)arene in situ followed by treatment with an electron-rich arene, such as anisole or thiophene, or with a functionalized arylstannane gave expedient regiospecific access to a wide range of functionally diverse diaryliodonium tosylates in moderate to high yields (44-98%). The described methodology broadens the scope for producing new functionalized diaryliodonium salts for diverse applications.

Rapid access to polycyclic N-heteroarenes from unactivated, simple azines via a base-promoted Minisci-type annulation.

Conventional synthetic methods to yield polycyclic heteroarenes have largely relied on metal-mediated arylation reactions requiring pre-functionalised substrates. However, the functionalisation of unactivated azines has been restricted because of their intrinsic low reactivity. Herein, we report a transition-metal-free, radical relay π-extension approach to produce N-doped polycyclic aromatic compounds directly from simple azines and cyclic iodonium salts. Mechanistic and electron paramagnetic resonance studies provide evidence for the in situ generation of organic electron donors, while chemical trapping and electrochemical experiments implicate an iodanyl radical intermediate serving as a formal biaryl radical equivalent. This intermediate, formed by one-electron reduction of the cyclic iodonium salt, acts as the key intermediate driving the Minisci-type arylation reaction. The synthetic utility of this radical-based annulative π-extension method is highlighted by the preparation of an N-doped heptacyclic nanographene fragment through fourfold C-H arylation.

11 C-Acetate PET/CT Detects Reactive Astrogliosis Helping Glioma Classification.

PURPOSE: 11 C-acetate ( 11 C-ACE) uptake on PET/CT was recently discovered to represent reactive astrocytes in the tumor microenvironment. This study aimed at evaluating the role of 11 C-ACE PET/CT as an imaging biomarker of reactive astrogliosis in characterizing different types of gliomas. METHODS: In this prospective study, a total of 182 patients underwent 11 C-ACE PET/CT before surgery. The ratio of SUV max of a glioma to the SUV mean of the contralateral choroid plexus ( 11 C-ACE TCR) on PET/CT was calculated. 11 C-ACE TCRs were compared with the World Health Organization grades and isocitrate dehydrogenase 1 ( IDH1 ) mutation status. Grade 2 was considered low-grade tumor, and grades 3 and 4 were considered high-grade tumors. RESULTS: The median 11 C-ACE TCR was significantly higher in IDH1 wild-type (wt) tumors (n = 91) than in IDH1 -mutant (mt) tumors (n = 91) (2.38 vs 1.30, P < 0.001). Of the 91 IDH1 -mt tumors, there were no differences in the median 11 C-ACE TCRs between oligodendrogliomas (ODs) and astrocytic tumors (1.40 vs 1.20, P > 0.05). In grading low- versus high-grade gliomas, the receiver operating characteristic curve analyses showed a higher area under the curve (0.951) in IDH1 -wt tumors than in IDH1 -mt tumors (0.783, P = 0.002). Grade 2 ODs were well differentiated from high-grade gliomas. The 11 C-ACE TCR of grade 3 ODs was significantly lower than that of IDH1 -wt glioblastomas. CONCLUSIONS: High 11 C-ACE uptake is associated with high-grade IDH1 -wt tumors, thus facilitating differentiation from high-grade IDH1-mt and low-grade gliomas. In particular, low 11 C-ACE uptake in ODs is advantageous in overcoming the limitation of radiolabeled amino acid tracers.

Syntheses of mGluR5 PET radioligands through the radiofluorination of diaryliodonium tosylates.

3-Fluoro-1-((thiazol-4-yl)ethynyl)benzenes constitute an important class of high-affinity metabotropic glutamate subtype 5 receptor (mGluR5) ligands, some of which have been labeled with fluorine-18 (t(1/2) = 109.7 min), to provide radioligands for molecular imaging of brain mGluR5 in living animal and human subjects with positron emission tomography (PET). Labeling in the 3-fluoro position of such ligands can be achieved through aromatic nucleophilic substitution of a halide leaving group with [(18)F]fluoride ion when a weakly activating m-nitrile group is present, but is generally very low yielding (<8%). Here we used a microfluidic reaction platform to show that greatly enhanced (up to 6-fold) radiochemical yields can be achieved from suitably synthesized diaryliodonium tosylate precursors. The presence of a m-nitrile or other activating group is not required. Similar conditions were adopted in a more conventional automated radiochemistry platform having a single-pot reactor, to produce mGluR5 radioligands with useful radioactivities for PET imaging.

Rapid and Efficient Radiosyntheses of Meta-substituted [F]Fluoroarenes from [F]Fluoride Ion and Diaryliodonium Tosylates within a Microreactor.

Effective methods for the introduction of the short-lived positron-emitter fluorine-18 (t(1/2) = 109.7 min) at high specific radioactivity into fluoroarenes are valuable for the development of radiotracers for molecular imaging with positron emission tomography. Here we have explored the scope of the radiofluorination of diaryliodonium salts with no-carrier-added [(18)F]fluoride ion for the preparation of otherwise difficult to access meta-substituted [(18)F]fluoroarenes. A microfluidic reaction platform was used to establish optimal radiochemical yields. Rapid, high yielding and selective radiofluorinations were achieved in unsymmetrical diaryliodonium tosylates (ArI(+)Ar'TsO(-)) in which Ar carried either a meta electron-withdrawing (CN, NO(2), CF(3)) or a meta electron-donating (Me or MeO) group, and in which the partner aryl group (Ar') was relatively electron-rich, such as Ph, 3-Me-C(6)H(4), 4-MeO-C(6)H(4), 2-thienyl or 5-Me-2-thienyl. The radiofluorination of appropriate diaryliodonium tosylates is therefore a generally useful method for the preparation of simple [(18)F]m-fluoroarenes ([(18)F]ArF).

Late-Stage 18F/19F Isotopic Exchange for the Synthesis of 18F-Labeled Sulfamoyl Fluorides.

Synthesis of sulfamoyl [18F]fluorides has been a challenging topic owing to the inefficient nucleophilic radiofluorination of sulfamoyl derivatives. Herein, we report an 18F/19F isotopic exchange approach to synthesize various sulfamoyl [18F]fluorides, otherwise inaccessible via direct synthesis from amines, with high radiochemical yields up to 97% (30 examples). This late-stage labeling protocol offers an efficient route to yield functionalized molecules by diversifying the chemical library possessing sulfamoyl functionalities through nucleophilic 18F incorporation within nitrogen-containing sulfur(VI) frameworks.