Structural disruption and alterations of synapses are associated with many brain disorders including Alzheimer's disease, epilepsy, depression, and schizophrenia. We have previously developed the PET radiotracer 11 C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in nonhuman primates and humans. Here we report the synthesis of a novel radiotracer 18 F-SDM-8 and its in vivo evaluation in rhesus monkeys. The in vitro binding assay of SDM-8 showed high SV2A binding affinity (K i = 0.58 nM). 18 F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (>98%). In the brain, 18 F-SDM-8 displayed very high uptake with peak standardized uptake value (SVU) greater than 8 and fast and reversible kinetics. A displacement study with levetiracetam and blocking studies with UCB-J and levetiracetam demonstrated its binding reversibility and specificity toward SV2A. Regional binding potential values were calculated and ranged from 0.8 in the brainstem to 4.5 in the cingulate cortex. By comparing to 11 C-UCB-J, 18 F-SDM-8 displayed the same attractive imaging properties: very high brain uptake, appropriate tissue kinetics, and high levels of specific binding. Given the longer half-life of F-18 and the feasibility for central production and multisite distribution, 18 F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders.

The use of synaptic vesicle protein 2A (SV2A) radiotracers with positron emission tomography (PET) imaging could provide a way to measure synaptic density quantitatively in living humans. 11 C-UCB-J, previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope 11 C. We developed a new tracer, an 18 F-labeled difluoro-analog of UCB-J ( 18 F-SynVesT-1, a.k.a. 18 F-SDM-8), which displayed favorable properties in monkeys. The purpose of this first-inhuman study was to assess the kinetic and binding properties of 18 F-SynVesT-1 and compare with 11 C-UCB-J.Methods: Eight healthy volunteers participated in a baseline study of 18 F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the anti-epileptic drug levetiracetam (20 mg/kg).Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were analyzed using one-and two-tissue compartment (1TC, 2TC) models and multilinear analysis 1 (MA1) to compute distribution volume (V T ) and binding potential (BP ND ). The centrum semiovale was used as a reference region. The Lassen plot was applied to compute levetiracetam occupancy and non-displaceable distribution volume (V ND ). Standardized uptake value ratio (SUVR) -1 over several time windows was compared with BP ND . Results: Regional TACs were fitted better with the 2TC model than the 1TC model, but 2TC V T estimates were unstable. The 1TC V T values matched well with those from the 2TC model (excluding the unstable values), Thus, 1TC was judged as the most useful model for quantitative analysis of 18 F-SynVesT-1 imaging data. Minimum scan time for stable V T measurement was 60 min. The rank order of V T and BP ND values was similar between 18 F-SynVesT-1 and 11 C-UCB-J.Regional V T values were slightly higher for 11 C-UCB-J, but BP ND values were higher for 18 F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of 18 F-SynVesT-1 in all regions and produced occupancy of 85.7%. SUVR-1 of 18 F-SynVesT-1 from 60-90 min matched best with 1TC BP ND . Conclusion:The novel SV2A tracer, 18 F-SynVesT-1, displays excellent kinetic and in vivo binding properties in humans and holds great potential for the imaging and quantification of synaptic density in neuropsychiatric disorders.

Synaptic vesicle glycoprotein 2A (SV2A) is expressed ubiquitously in neurons of the central nervous system, and is the binding target of the anti-epileptic drug levetiracetam. Because of the availability of positron emission tomography (PET) ligands targeting SV2A, there is increasing enthusiasm on the use of SV2A PET to study a variety of neuropsychiatric diseases. This review discusses the recent development of radioligands for PET imaging of SV2A and their potential use in the research and diagnosis of CNS diseases.

The development of chelating agents for copper radionuclides in positron emission tomography radiopharmaceuticals has been a highly active and important area of study in recent years. The rapid evolution of chelators has resulted in highly specific copper chelators that can be readily conjugated to biomolecules and efficiently radiolabeled to form stable complexes in vivo. Chelators are not only designed for conjugation to monovalent biomolecules but also for incorporation into multivalent targeting ligands such as theranostic nanoparticles. These advancements have strengthened the role of copper radionuclides in the fields of nuclear medicine and molecular imaging. This review emphasizes developments of new copper chelators that have most greatly advanced the field of copper-based radiopharmaceuticals over the past 5 years.

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer’s disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer–induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [ 18 F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD ( APPswe/PS1 Δ E9 overexpressing transgenic and App NL-G-F / hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [ 18 F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents.

11 C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted 11 C-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD) and found a 41% decrease in specific binding in the hippocampus compared with healthy subjects. We hypothesized that 11 C-UCB-J may have potential to be a general biomarker for evaluating AD treatment effects via monitoring of synaptic density changes. In this study, we performed longitudinal 11 C-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Methods: Nine wildtype (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1DE9 [APP/PS1]) mice underwent 3 11 C-UCB-J PET measurements: at baseline, after treatment, and during drug washout. After baseline measurements, saracatinib, a Fyn kinase inhibitor currently in clinical development for AD treatment, was administered by oral gavage for 41 ± 11 d. Treatmentphase measurements were performed on the last day of treatment, and washout-phase measurements occurred more than 27 d after the end of treatment. SUVs from 30 to 60 min after injection of 11 C-UCB-J were calculated and normalized by the whole-brain (WB) or brain stem (BS) average values as SUV ratio (SUVR (WB) or SUVR-1 (BS)). Results: Hippocampal SUVR (WB) at baseline was significantly lower in APP/PS1 than WT mice (APP/PS1: 1.11 ± 0.04, WT: 1.15 ± 0.02, P 5 0.033, unpaired t test). Using SUVR-1 (BS) in the hippocampus, there was also a significant difference at baseline (APP/ PS1: 0.48 ± 0.13, WT: 0.65 ± 0.10, P 5 0.017, unpaired t test). After treatment with saracatinib, hippocampal SUVR (WB) in APP/PS1 mice was significantly increased (P 5 0.037, paired t test). A trend-level treatment effect was seen with hippocampal SUVR-1 (BS). Saracatinib treatment effects may persist, as there were no significant differences between WT and APP/PS1 mice after drug washout. Conclusion: On the basis of the 11 C-UCB-J PET results, hippocampal synaptic density was lower in APP/PS1 mice than in WT mice at baseline, and this deficit was normalized by treatment with saracatinib. These results support the use of 11 C-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD.

The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation ofF-LY2459989 as the first F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison withC-LY2459989. The novel radioligandF-LY2459989 was synthesized by F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and the calculation of binding parameters. With the iodonium ylide precursor, F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; = 6). In monkeys,F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of F-LY2459989 in vivo. Regional time-activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex> insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. The evaluation ofF-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of F-LY2459989 andC-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.

Glioblastoma multiforme (GBM) is the deadliest type of brain tumor, affecting approximately three in 100,000 adults annually. Positron emission tomography (PET) imaging provides an important non-invasive method of measuring biochemically specific targets at GBM lesions. These powerful data can characterize tumors, predict treatment effectiveness, and monitor treatment. This review will discuss the PET imaging agents that have already been evaluated in GBM patients so far, and new imaging targets with promise for future use. Previously used PET imaging agents include the tracers for markers of proliferation ([11C]methionine; [18F]fluoro-ethyl-L-tyrosine, [18F]Fluorodopa, [18F]fluoro-thymidine, and [18F]clofarabine), hypoxia sensing ([18F]FMISO, [18F]FET-NIM, [18F]EF5, [18F]HX4, and [64Cu]ATSM), and ligands for inflammation. As cancer therapeutics evolve toward personalized medicine and therapies centered on tumor biomarkers, the development of complimentary selective PET agents can dramatically enhance these efforts. Newer biomarkers for GBM PET imaging are discussed, with some already in use for PET imaging other cancers and neurological disorders. These targets include Sigma 1, Sigma 2, programmed death ligand 1, poly-ADP-ribose polymerase, and isocitrate dehydrogenase. For GBM, these imaging agents come with additional considerations such as blood–brain barrier penetration, quantitative modeling approaches, and nonspecific binding.