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Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [ 18 F] 10 and [ 18 F] 15 ([ 18 F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [ 18 F] 15 demonstrated a better performance. In conclusion, [ 18 F] 15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.

Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. In vivo imaging of SV2A using PET has potential applications in the diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, autism, epilepsy, stroke, traumatic brain injury, post-traumatic stress disorder, depression, etc. Herein, we report the synthesis and evaluation of a new 18 F-labeled SV2A PET imaging probe, [ 18 F]SynVesT-2, which possesses fast in vivo binding kinetics and high specific binding signals in non-human primate brain.

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 blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies., Competing Interests: Competing financial interests: The authors declare no competing financial interests.

The avidin-biotin interaction permits rapid and nearly irreversible noncovalent linkage between biotinylated molecules and avidin-modified substrates. We designed a biotinylated radioligand intended for use in the detection of avidin-modified polymer nanoparticles in tissue with positron emission tomography (PET). Using an F-18 labeled prosthetic group, [(18)F]4-fluorobenzylamine, and a commercially available biotin derivate, NHS-PEG4-biotin, [(18)F]-fluorobenzylamide-poly(ethylene glycol)4-biotin ([(18)F]NPB4) was prepared with high purity and specific activity. The attachment of the [(18)F]NPB4 radioligand to avidin-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles was tested by using PET imaging to measure the kinetics of convection-enhanced delivery (CED) of nanoparticles of varying size to the rat brain. PET imaging enabled the direct observation of nanoparticle delivery by measurement of the spatial volume of distribution of radiolabeled nanoparticles as a function of time, both during and after the infusion. This work thus validates new methods for radiolabeling PEG-biotin derivatives and also provides insight into the fate of nanoparticles that have been infused directly into the brain.

We have synthesized five fluorinated derivatives of WAY 100635, N-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-N-(2-pyridyl)cyclohe xaneca rboxamide (4a), using various acids in place of the cyclohexanecarboxylic acid (CHCA, 2a) in the reaction scheme. The five acids are 4-fluorobenzoic acid (FB, 2b), 4-fluoro-3-methylbenzoic acid (MeFB, 2c), trans-4-fluorocyclohexanecarboxylic acid (FC, 2d), 4-(fluoromethyl)benzoic acid (FMeB, 2e), and 3-nitro-4-(fluoromethyl)benzoic acid (NFMeB, 2f) (see Scheme 1). These compounds were radiolabeled with fluorine-18, and their biological properties were evaluated in rats and compared with those of [11C]carbonyl WAY 100635 ([carbonyl-11C]4a). [Carbonyl-11C]4a cleared the brain with a biological half-life averaging 41 min. The metabolite-corrected blood radioactivity had a half-life of 29 min. [18F]FCWAY ([18F]4d) gave half-lives and intercepts comparable to [carbonyl-11C]4a in the brain, but the blood clearance was faster. [18F]FBWAY ([18F]4b) showed an early rapid net efflux from the whole brain, clearing with a biological half-life of 35 min. The metabolite-corrected blood half-life was 41 min. The comparable whole brain and blood half-lives for Me[18F]FBWAY ([18F]4c) were 16 and 18 min, respectively. For each compound, the corresponding carboxylic acid was identified as a major metabolite in blood. Fluoride was also found after injection of [18F]4d. However, for all compounds there was a good correlation (R > 0.97) between the differential uptake ratio (DUR, (%ID/g) x body weight (g)/100) in individual rat brain regions at 30 min after injection and the concentration of receptors as determined by in vitro quantitative autoradiography in rat. Specific binding ratios [region of interest (ROI)/cerebellum-1] in control studies for cortex (Ctx) and hippocampus (H) were higher for [carbonyl-11C]4a and [18F]4d compared to [18F]4b and [18F]4c. [18F]4d has similar pharmacokinetic properties and comparable specific binding ratios to [carbonyl-11C]4a. Fifty nanomoles of 4a blocked only 30% of the specific binding of [18F]4d, while complete blockade was obtained from co-injection of 200 nmol of 4a (H/Cb-1 from 17.2 to 0.6). [18F]4b and [18F]4c showed lower specific binding ratios than [carbonyl-11C]4a and [18F]4d. [18F]4c was superior to [18F]4b since its specific binding was more readily blocked by 4a. These studies suggest that [18F]4c should be a useful compound to assess dynamic changes in serotonin levels while [18F]4d, with its high contrast and F-18 label, should provide better statistics and quantification for static measurement of 5-HT1A receptor distribution.