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Abstract: Alzheimer’s Disease (AD), a progressive and irreversible neurodegenerative disorder, is the most common form of dementia worldwide. Currently, there is no disease-modifying AD drug, and the development of effective treatments is made even harder by the highly selective nature of the Blood-Brain Barrier (BBB) that allows the passage only of molecules with specific chemical-- physical properties. In this context, nanomedicine and its Nanoparticles (NPs) offer potential solutions to the challenge of AD therapy, in particular, the requirements for i) BBB crossing, ii) multitarget therapy iii) enhancement of pharmacokinetics; and iv) more precise delivery. In addition, the possibility to optimize NP biophysical and biological (i.e. target-specific ligands) properties allows for highly tailored delivery platforms. Preclinical studies have demonstrated that nanotherapeutics provide superior pharmacokinetics and brain uptake than free drugs and, on the other hand, these are also able to mitigate the side-effects of the symptomatic treatments approved by the FDA. Among the plethora of potential AD nanodrugs, multitarget nanotherapeutics are considered the most promising strategy due to their ability to hit simultaneously multiple pathogenic factors, while nano-nutraceuticals are emerging as interesting tools in the treatment/prevention of AD. This review provides a comprehensive overview of nanomedicine in AD therapy, focusing on key optimization of NPs properties, most promising nanotherapeutics in preclinical studies and difficulties that are limiting the efficient translation from bench to bedside.

Claudin-5 is the dominant tight junction protein in brain endothelial cells and exclusively limits the paracellular permeability of molecules larger than 400 Da across the blood-brain barrier (BBB). Its pathological impairment or sustained down-regulation has been shown to lead to the progression of psychiatric and neurological disorders, whereas its expression under physiological conditions prevents the passage of drugs across the BBB. While claudin-5 enhancers could potentially act as vascular stabilizers to treat neurological diseases, claudin-5 inhibitors could function as delivery systems to enhance the brain uptake of hydrophilic small-molecular-weight drugs. Therefore, the effects of claudin-5 manipulation on modulating the BBB in different neurological diseases requires further examination. To manipulate claudin-5 expression levels and function, several claudin-5 modulating molecules have been developed. In this review, we first describe the molecular, cellular and pathological aspects of claudin-5 to highlight the mechanisms of claudin-5 enhancers/inhibitors. We then discuss recently developed claudin-5 enhancers/inhibitors and new methods to discover these molecules.

The first candidate PI-2014 was tested in healthy controls and subjects with Alzheimer's disease (AD). As PI-2014 displayed off-target binding to monoamine oxidase A (MAO-A), a new lead with improved binding to Tau and decreased MAO-A binding was required. For compound optimization, Tau binding assays based on both human AD brain homogenate and Tau-paired helical filaments were employed. Furthermore, two MAO-A screening assays based on (1) human-recombinant MAO-A and (2) displacement of 2-fluoro-ethyl-harmine from mouse brain homogenate were employed. Removing the N-methyl group from the tricyclic core resulted in compounds displaying improved Tau binding. For the final round of optimization, the cyclic amine substituents were replaced by pyridine derivatives. PI-2620 (2-(2-fluoropyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine) emerged as a best candidate displaying high Tau binding, low MAO-A binding, high brain uptake, and fast and complete brain washout. Furthermore, PI-2620 showed Tau binding on brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick's disease.

Introduction Aging is an inevitable physiological process and the biggest risk factor of Alzheimer's disease (AD). Developing an imaging tracer to visualize aging-related changes in the brain may provide a useful biomarker in elucidating neuroanatomical mechanisms of AD. Methods We developed and characterized a new tracer that can be used to visualize SIRT1 in brains related to aging and AD by positron emission tomography imaging. Results The SIRT1 tracer displayed desirable brain uptake and selectivity, as well as stable metabolism and proper kinetics and distribution in rodent and nonhuman primate brains. This new tracer was further validated by visualizing SIRT1 in brains of AD transgenic mice, compared to nontransgenic animals. Discussion Our SIRT1 tracer not only enables, for the first time, the demonstration of SIRT1 in animal brains, but also allows visualization and recapitulation of AD-related SIRT1 neuropathological changes in animal brains.

Introduction Takotsubo syndrome (TTS) is triggered mostly by physical and/or emotional stress that is processed in stress-associated brain regions, including the amygdala. However, it remains unclear whether such stress-induced brain activity is associated with TTS onset. Methods and results We acquired brain [18F]-2-fluoro-deoxy- d -glucose (18F-FDG) positron emission tomography in 4 TTS patients (44–82 yrs., 3 women) on days 2–4 (acute phase) and days 29–40 (recovery phase) after diagnosis of TTS was made by coronary angiography and left ventriculogram. The 18F-FDG uptake was measured globally and also in the pre-defined regions of interest of the bilateral amygdala on the common Montreal Neurological Institute space; all 18F-FDG images were normalized using automated image pre-processing. Amygdalar activity was calculated by dividing the 18F-FDG uptake of the amygdala by the global brain uptake. Left ventriculograms showed that apical ballooning was typical at diagnosis and was then relieved in the recovery phase. Amygdalar activity in the acute phase (0.872 ± 0.032) was higher than in the recovery phase (0.805 ± 0.037) (P = 0.013). Conclusions We report here 4 cases of TTS showing higher amygdalar activity in the acute phase as compared with the recovery phase, suggesting that increased stress-induced neurobiological activity is associated with TTS onset.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [3H]CBD-2115 had a KD value of 6.9 nM and a nominal Bmax of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [3H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [3H]flortaucipir (45 nM) or [3H]MK-6240 (>50 nM). [18F]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5-0.65 standardized uptake value with fast clearance from normal tissues. [3H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

[Image: see text] Noninvasive imaging of tau aggregates with a positron emission tomography (PET) tracer is useful for the diagnosis and staging of Alzheimer’s disease (AD). Recently, we found that benzimidazopyridine (BIP) is an attractive scaffold for developing PET and single photon computed emission tomography tracers targeting tau aggregates. In this study, we designed and synthesized five novel (18)F-labeled compounds with various substituted groups or atoms at the 7-position of the BIP scaffold. In in vitro autoradiographic studies, all (18)F-labeled BIP derivatives selectively bound to tau aggregates deposited in AD brain sections. On the other hand, the initial brain uptake of these compounds was affected by the type of substituted group or halogen atom introduced into the 7-position of the BIP scaffold. Among these compounds, [(18)F]Me-BIPF showed the highest brain uptake (6.79% ID/g at 2 min postinjection) and 2 min/60 min ratio (3.59). These results suggest that appropriate introduction of the substituted group or atom into the 7-position of the BIP scaffold may be effective for developing useful tau PET tracers.

Development of brain therapeutics is significantly hampered by the presence of the blood-brain barrier (BBB). Classical transwell models are able to recapitulate many important aspects of drug transport across the BBB, but are not completely predictive of in vivo brain uptake. Species differences further complicate translation of experimental therapeutics from the benchtop to the clinic. Human BBB models offer some solutions to this problem, and by increasing device complexity both in terms of multicellularity, flow and physical architecture, physiological models of the BBB have been developed that can more faithfully model different aspects of transport and homeostasis BBB. Using these models, it may be possible to improve the predictive capacity in benchmarking candidate therapeutics, and to identify new druggable targets by studying multicellular interactions.

For the treatment of cerebral ischaemia, vitamin-D3 loaded nanoemulsions were developed. Tween 20 and polyethylene glycol were chosen as surfactant/co-surfactant, while oleic acid as the oil phase....

Accidental intoxications from environmental pollutants, as well as intentional self- and chemical warfare-related poisonings affect millions of people worldwide each year. While many toxic agents can readily enter the central nervous system (CNS), the blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. Consequently, poisoning antidotes usually cannot reach their site of action in the CNS in therapeutically relevant concentrations, and thus only provide effective protection to the peripheral nervous system. This limitation can be overcome by encapsulating the antidotes in nanoparticles (NP), which can enhance their CNS accumulation without damaging the integrity of the BBB. Among nanocarriers, polymer-based drug delivery systems exhibit remarkable benefits, such as bioavailability, cell uptake and tissue retention. Furthermore, due to their capacity to mask unfavorable physicochemical properties of cargo drugs, polymeric NPs were able to improve BBB transport of various pharmaceuticals. However, while polymer NP-mediated treatment of various pathological brain conditions, such as glioma and Alzheimer's disease were exhaustively studied, the application of polymeric nanocarriers for brain-targeted delivery of antidote molecules has not been adequately examined. To display its therapeutic potential, we review the state of the art of polymer NP-assisted CNS delivery of antidotes for various poisonings, including heavy metal and organophosphorus intoxications.

β-Amyloid (Aβ) plaques and Tau tangles are cognitive impairment markers vital for diagnosing and preventing Alzheimer's disease (AD). To systematically explore the relationship between the number or position of nitrogen atoms and their optical properties and biological properties, five series of new N, O-coordinated organo-difluoroboron probes were introduced as binding scaffolds for Aβ plaques and Tau tangles. These probes exhibited suitable optical properties for near-infrared (NIR) imaging. Probe 4PmNO-2 (4-((1E,3E)-4-(1,1-difluoro-1H-1λ4,9λ4-pyrimido[1,6-c][1,3,5,2]oxadiazaborinin-3-yl)buta-1,3-dien-1-yl)-N,N-dimethylaniline) displayed the excellent emission maximum (716 nm in PBS), a high quantum yield (61.4% in CH2Cl2), and a high affinity for synthetic Aβ1–42 (Kd = 23.64 ± 1.08 nM) and Tau (K18) aggregates (Kd = 26.38 ± 1.29 nM), as well as for native Aβ plaques and NFTs in the brain tissue from AD patients. 4PmNO-2, with significantly enhanced fluorescence (Aβ1–42, 136 fold; Tau (K18), 96 fold) and the highest initial brain uptake (11.57% ID/g at 2 min) in normal ICR mice, was evaluated further. In vivo NIR fluorescent imaging studies in living Aβ and Tau transgenic mice revealed that it could differentiate healthy and diseased animals. Further ex vivo fluorescent staining studies showed that 4PmNO-2 specifically bound to Aβ plaques and Tau tangles in transgenic mice. In summary, the probe 4PmNO-2 may be a useful near-infrared fluorescence (NIRF) probe for AD biomarkers.

This study presents [99mTc]BPTG-1 and [99mTc]BPTG-2 for glioblastoma imaging. In vitro cellular uptakes of these radiotracers were examined in SKOV-3, MCF-7, U87-MG, HT-29, and A549 cell lines. U87-MG cell line displayed the highest radiotracers uptakes. Biodistribution study in U87-MG tumor bearing mice revealed higher uptake of radiotracers in tumor than muscle and brain. Liver, intestine, and kidneys displayed the highest radioactivity uptakes. The main route of radiotracers elimination was hepatobiliary. Due to the brain uptake of these radiotracers, they are promising radiotracers for future studies in the diagnosis of glioblastoma.

1. Donepezil (DPZ) is an acetylcholinesterase (AchE) inhibitor used in the mild to moderately severe Alzheimer’s disease. Among its major metabolites, 6-O-desmethyl DPZ (6-DDPZ), 5-O-desmethyl DPZ ...

Carbon-11 labeled SL25.1188 is a promising reversible monoamine oxidase-B (MAO-B) radioligand that was recently translated for human positron emission tomography (PET) imaging. Herein, we report the development of a novel fluorinated derivative, namely, [18F](S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one ([18F]FSL25.1188; [18F]6), as a candidate 18F-labeled MAO-B radioligand, and, its subsequent preclinical evaluation in non-human primates (NHP). [18F]6 was produced and isolated (>6 GBq) with high radiochemical purity (>99%), and molar activity (>100 GBq/µmol at time of injection). Autoradiography studies conducted in post-mortem human brain sections revealed [18F]6 binding in MAO-B rich regions. PET imaging study of [18F]6 in NHP showed high brain uptake (SUV > 2.5) as well as a regional brain radioactivity distribution in accordance with MAO-B expression. [18F]6 displayed favorable in vivo kinetics, with an early peak in the time-activity curve followed by progressive wash-out from the NHP brain. Specificity of [18F]6 was investigated in a pre-treatment study with l -deprenyl (1.0 mg/kg) wherein reduced radioligand uptake was observed in all MAO-B rich regions. Results from the current preclinical investigation suggests [18F]6 is a promising MAO-B PET radioligand. Further evaluation of [18F]6 and structurally related 18F-analogs are underway to identify an optimized candidate for clinical research studies.

Here, we report the development of novel PET radiotracer ([11C]CW22) of BET proteins. In vivo imaging results in rodents and nonhuman primates (NHP) demonstrate that [11C]CW22 has excellent brain uptake, good specificity, good selectivity, suitable metabolism, appropriate kinetics and distribution in the brain. Our studies demonstrated that [11C]CW22 exhibits ideal properties as a PET imaging probe of BET proteins for further validation.

Comparing MRI and histopathology, this study aims to comprehensively explore the potential application of 18F-trifluoromethylated D-cysteine (S-[18F]CF3-D-CYS) in evaluating glioma by using orthotopic C6 glioma models. Sprague–Dawley (SD) rats (n = 9) were implanted with C6 glioma cells. Tumor growth was monitored every week by multiparameter MRI [including dynamic contrast-enhanced MRI (DCE-MRI)], [18F]FDG, S-[18F]CF3-D-CYS, and [18F]FDOPA PET imaging. Repeated scans of the same rat with the two or three [18F]-labeled radiotracers were investigated. Initial regions of interest were manually delineated on T2WI and set on the same level of PET images, and tumor-to-normal brain uptake ratios (TNRs) were calculated to semiquantitatively assess the tracer accumulation in the tumor. The tumor volume in PET and histopathology was calculated. HE and Ki67 immunohistochemical staining were further performed. The correlations between the uptake of S-[18F]CF3-D-CYS and Ki67 were analyzed. Dynamic S-[18F]CF3-D-CYS PET imaging showed tumor uptake rapidly reached a peak, maintained plateau during 10–30 min after injection, then decreased slowly. Compared with [18F]FDG and [18F]FDOPA PET imaging, S-[18F]CF3-D-CYS PET demonstrated the highest TNRs (P < 0.05). There were no significant differences in the tumor volume measured on S-[18F]CF3-D-CYS PET or HE specimen. Furthermore, our results showed that the uptake of S-[18F]CF3-D-CYS was significantly positively correlated with tumor Ki67, and the poor accumulated S-[18F]CF3-D-CYS was consistent with tumor hemorrhage. There was no significant correlation between the S-[18F]CF3-D-CYS uptakes and the Ktrans values derived from DCE-MRI. In comparison with MRI and histopathology, S-[18F]CF3-D-CYS PET performs well in the diagnosis and evaluation of glioma. S-[18F]CF3-D-CYS PET may serve as a valuable tool in the clinical management of gliomas.

Olfactory pathway as a viable route for brain uptake of environmental pollutants has been hypothesized in past decade. In such a hypothesis, subclinical low-dose exposure and chronic brain accumulation of exogenous airborne agents are critical to define neurodegenerations, however the information is extremely lacking. Advances in granular measurement of air pollutants, real-time personal exposure monitoring and big data analytics have opened-up an unprecedented opportunity to enable researchers conduct longitudinal investigation and potentially link the external environment condition to risks of human developing neurodegenerative diseases in a foreseeable future. Detailed case studies are provided in this work that illustrate the quantification of human brain accumulation of ultrafine particles (UFPs) from exposure, surface deposition, and pathway penetration via the transport route of nasal olfactory in prolonged timespans. The study links the individual components along the olfactory pathway, showcases the available research capacity, and pinpoints the critical areas of research need in environmental, toxicological and epidemiological studies, significant to a joint effort to bring together an interdisciplinary solution to uncover the insight of time course and dose dependency between environmental exposure and risk of developing neurodegenerative diseases in a foreseeable future. It should be noted that current study assumes that nanoparticle penetration along the olfactory pathway is unidirectional and follows the rate observed in the rodent study. Tissue responses in determining the penetration and retention corresponding to size and composition of the inhaled nanoparticles are not considered.

Brain scans have been conducted using gamma camera to determine the brain uptake value from anterior-posterior and lateral images and determine the correlation between injection dose, age, and Body Mass Index (BMI) on brain uptake. This study was performed on six volunteers with an average age of 58 ± 1 years old. Brain scans were performed using a dual-headed gamma camera, and the static images were obtained from anterior-posterior and lateral positions. In this study, the radioisotope was Tc99m mixed with Hexamethyl Propyleneamine Oxime (HMPAO) cold kit pharmaceutical. The average injection dose given to volunteers was 13.35 ± 1.59 mCi. Radiopharmaceutical was administered to volunteers through intravenous injection. 99mTc HMPAO inside the body will emit gamma radiation that will be detected by a gamma camera to produce images of the observed organ. The counts were obtained using segmentation of freehand region-of-interest (ROI) to obtain brain uptake value. The results showed that the uptake mean value from the anterior-posterior image was 3.11%, and the lateral image was 3.19%, respectively. The injection dose and age showed a weak correlation with brain uptake value, while BMI showed an inversely moderate correlation with 99mTc HMPAO uptake value.

Peripheral and central administration of glucose potently enhance cognitive functions. The present experiments examined changes in brain extracellular glucose levels while rats were trained to solve hippocampus-sensitive place or striatum-sensitive response learning tasks for food or water reward. During the first minutes of either place or response training, extracellular glucose levels declined in both the hippocampus and striatum, an effect not seen in untrained, rewarded rats. Subsequently, glucose increased in both brain areas under all training conditions, approaching asymptotic levels ∼15-25 min into training. Compared to untrained-food controls, training with food reward resulted in significant glucose increases in the hippocampus but not striatum; striatal glucose levels exhibited large increases to food intake in both trained and untrained groups. In rats trained to find water, glucose levels increased significantly above the values seen in untrained rats in both hippocampus and striatum. In contrast to results seen with lactate measurements, the magnitude of training-related increases in hippocampus and striatum glucose levels did not differ by task under either reward condition. The decreases in glucose early in training might reflect an increase in brain glucose consumption, perhaps triggering increased brain uptake of glucose from blood, as evident in the increases in glucose later in training. Together with past findings measuring lactate levels under the same conditions, the initial decreases in glucose may also stimulate increased production of lactate from astrocytes to support neural metabolism directly and/or to act as a signal to increase blood flow and glucose uptake into the brain.HighlightsGlucose levels in hippocampus and striatum decrease at the start of training.Glucose levels increase in both brain areas later in training.Glucose changes in both brain areas were similar for place and response tasks.Glucose levels responded similarly to training for either food and water rewards.Early decreases in glucose may trigger increased production astrocytic lactate.

A 76-year-old man with a prior medical history of resected malignant melanoma of the skull underwent Ga-prostate-specific membrane antigen (PSMA) PET/CT due to rising tumor markers of a known prostate carcinoma. Unexpected high Ga-PSMA brain uptake was encountered around the surgical cavity in the skull with initially no specific structural changes on anatomical imaging. Successive CT and MRI eventually revealed local melanoma brain recurrence at this site. This interesting case demonstrates the diagnostic potential of Ga-PSMA PET/CT imaging for detection of malignant melanoma brain recurrence.

Herein, we report to the best of our knowledge the first 64Cu PET imaging agent that shows appreciable in vivo brain uptake and exhibits high specific affinity for beta-amyloid (Aβ) aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of WT mice. The employed approach uses a bifunctional chelator with two Aβ-interacting fragments that dramatically improves the Aβ-binding affinity and lipophilicity for favorable BBB penetration, while the use of optimized-length spacers between the Cu-chelating group and the Aβ-interacting fragments further improves the in vivo Aβ-binding specificity and brain uptake of the corresponding 64Cu PET imaging agent.

PET scans of the mouse brain are usually performed with anesthesia to immobilize the animal. However, it is desirable to avoid the confounding factor of anesthesia in mouse-brain response. Methods: We developed and validated brain PET imaging of awake, freely moving mice. Head-motion tracking was performed using radioactive point-source markers, and we used the tracking information for PET-image motion correction. Regional F-18-FDG brain uptake in a test, retest, and memantine-challenge study was measured in awake (n = 8) and anesthetized (n = 8) C57BL/6 mice. An awake uptake period was considered for the anesthesia scans. Results: Awake (motion-corrected) PET images showed an F-18-FDG uptake pattern comparable to the pattern of anesthetized mice. The test-retest variability (represented by the intraclass correlation coefficient) of the regional SUV quantification in the awake animals (0.424-0.555) was marginally lower than that in the anesthetized animals (intraclass correlation coefficient, 0.491-0.629) over the different regions. The increased memantine-induced F-18-FDG uptake was more pronounced in awake (+63.6%) than in anesthetized (+24.2%) animals. Additional behavioral information, acquired for awake animals, showed increased motor activity on a memantine challenge (total distance traveled, 18.2 +/- 5.28 m) compared with test-retest (6.49 +/- 2.21 m). Conclusion: The present method enables brain PET imaging on awake mice, thereby avoiding the confounding effects of anesthesia on the PET reading. It allows the simultaneous measurement of behavioral information during PET acquisitions. The method does not require any additional hardware, and it can be deployed in typical high-throughput scan protocols.

Copper-mediated 11C-cyanation reactions have enabled the synthesis of PET radiotracers from a range of readily available precursors and avoid the need to use more toxic Pd catalysts. In this work we adapt our recently developed 11C-cyanation of arylpinacolboronate (BPin) esters for the cGMP synthesis of [11C]LY2795050, a selective antagonist radiotracer for the kappa opioid receptor (KOR). [11C]LY2795050 was synthesized in 6 ± 1% noncorrected radiochemical yield (based on [11C]HCN, n = 3) using an automated synthesis module. Quality control testing confirmed the suitability of doses for preclinical and clinical PET imaging (radiochemical purity >99%; specific activity >900 mCi/μmol; residual Cu < 0.1 μg/mL). PET imaging was conducted in rodent and nonhuman primates, showing good brain uptake of [11C]LY2795050 and the expected distribution of KOR. Analogous imaging with [11C]carfentanil (a selective mu opioid receptor (MOR) radiotracer) revealed the anticipated regional differences in MOR and KOR distribution in the primate brain.

4-{(4-Methylphenyl)glycyl}-3,4-dihydroquinoxalin-2(1H)-one (QIN) was prepared from 4-(2-chloroacetyl)- 3,4-dihydroquinoxalin-1(1H)-one). 125I-QIN was prepared by electrophilic substitution using Chloramine- T as an oxidizing agent. The highest labeling yield, 94%, was obtained under the following conditions: pH 7, 15 min, 100 μg of QIN, 50 μg of Chloramine-T, and carrier-free Na125I. The labeled compound was stable for up to 12 h post labeling. A biodistribution study of 125I-QIN in mice showed that its brain uptake was about 5.1% at 30 min post injection and remained on this level up to 1 h. As compared to commercially used radiopharmaceuticals for brain imaging, 125I-QIN is more stable and shows higher brain uptake.

One of the major challenges in drug development is the delivery of therapeutics to the central nervous system (CNS). The blood-brain barrier (BBB), which modulates the passage of molecules from the CNS, presents a formidable obstacle that limits brain uptake of therapeutics and, therefore, impedes the treatment of multiple neurological pathologies. Targeted nanocarriers present an excellent opportunity for drug delivery into the brain leveraging on endogenous receptors to transport therapeutics across the BBB endothelium. Receptor-mediated transport endows multiple benefits over other conventional delivery methods such as the transient permeabilization of the BBB or the direct depositioning of intracranial depots. Herein, different strategies for nanocarrier targeting to the CNS are discussed, highlighting the challenges and recent developments.

Aim: To enhance the bioavailability and brain uptake of probucol and examine whether it attenuates neuroinflammation and neurodegeneration by utilizing a sodium alginate nanoencapsulation technique. Materials & methods: Wild-type mice were given either low-fat standard chow, high-fat (HF) diet to induce neuroinflammation and neurodegeneration, HF diet supplemented with nanocapsuled probucol at a concentration of 0.1% (w/w), HF diet supplemented with noncapsulated probucol at the same concentration of 0.1%, or HF diet supplemented with noncapsulated probucol at higher concentration (1%) for 24 weeks. Results & conclusion: The nanoencapsulation increased the plasma and brain concentration of probucol significantly compared with the mice that was given the same dosage of probucol without capsulation, and significantly suppressed the neuroinflammation and neurodegeneration.

The drug delivery across the brain has always been problematic due to the tight junction present namely the blood brain barrier (BBB). BBB only allows selected pharmaceutical drugs to get across it and reach the brain via lipid free diffusion process and exert their therapeutic effect. This leads to the decrease in drug accessibility to brain. More recently, various approaches were employed to allow larger molecules to cross BBB by reengineering them and conjugating them with ligands which could facilitate their entry across BBB. Therefore literature was explicitly exploited to deduce various ligands employed to enhance the drug delivery across brain via transcytosis. As per established literature, there are evidences that ligand conjugated drug formulations have substantially improved brain uptake. The review presents numerous ligands employed along with the receptor targeted to improve drug uptake by the brain, its anticipated effects and the outcome derived.

Among small, hydrophilic drug-like molecules, [14C]sucrose has long been considered the gold standard for determination of blood-brain barrier permeability. However, we have recently shown in rats that, compared with liquid chromatography–tandem mass spectrometry analysis of stable isotope (13C) of sucrose, [14C]sucrose significantly overestimates the brain tissue concentration and uptake of sucrose by a factor of 6 to 7. This discrepancy is due to the presence of small quantities of lipophilic impurities in [14C]sucrose tracer solutions. Here, we used intracranial microdialysis to measure concentrations of both sucrose variants in brain extracellular fluid (ECF) after intravenous bolus administration to mice. Both markers displayed similar plasma profiles and ECF dialysate concentrations. However, total brain tissue concentrations and apparent brain uptake clearance of [14C]sucrose were 4.1- and 3.6-fold higher, respectively, than those of [13C]sucrose. Therefore, the contaminants of [14C]sucrose with higher permeability were likely sequestered by brain cells, which renders them nondialyzable. It is concluded that although measurement of radioactivity overestimates the concentrations of intact sucrose in the brain tissue, the ECF radioactivity after microdialysis is a relatively accurate reflection of intact sucrose after the systemic administration of the [14C]sucrose marker.

Lipid microparticles (LMs) uncoated or coated with chitosan and containing the neuroprotective polyphenol resveratrol were developed for its targeting to the brain via nasal administration. The lipid microparticles loaded with resveratrol (LMs-Res) were produced by melt emulsification, using stearic acid as lipid material and phosphatidylcholine as the surfactant. The chitosan coated particles LMs-Res-Ch (1.75% w/v chitosan solution) and LMs-Res-Ch-plus (8.75% w/v chitosan solution) were prepared by adding a chitosan solution to the formed particles. The mean diameter of the particles were 68.5 ± 3.1 μm, 76.3 ± 5.2 μm and 84.5 ± 8.1 μm for LMs-Res, LMs-Res-Ch and LMs-Res-Ch-plus respectively, suitable for nasal delivery. Chitosan coating changed the particle surface charge from a negative zeta potential value (−12.7 ± 2.1 mV) for the uncoated particles to a higher positive values respectively, 24.0 ± 4.7 and 44.6 ± 3.1 mV for the chitosan coated LM-Res-Ch and LM-Res-Ch-plus. Permeation studies across human NCM460 cell monolayers demonstrated that their transepithelial electrical resistance (TEER) values were not modified in the presence of free resveratrol, unloaded LMs, loaded LMs-Res or LMs-Res-Ch. On the other hand, the TEER values decreased from 150 ± 7 to 41 ± 3 Ω cm2 in the presence of LMs-Res-Ch-plus, which corresponded to a significant increase in the apparent permeability (Papp) of resveratrol from 518 ± 8 × 10−4 cm/min to 750 ± 98 × 10−4 cm/min. In vivo studies demonstrated that no resveratrol was detected in the rat cerebrospinal fluid (CSF) after an intravenous infusion of the polyphenol. Conversely, the nasal delivery of resveratrol in a chitosan suspension or encapsulated in uncoated LMs-Res dispersed in water achieved the uptake of resveratrol in the CSF with Cmax after 60 min of 1.30 ± 0.30 μg/ml and 0.79 ± 0.15 μg/ml, respectively. However, a dramatic increase in the levels of resveratrol reaching the CSF was attained by the administration of an aqueous suspension of LMs-Res-Ch-plus with a Cmax after 60 min of 9.7 ± 1.9 μg/ml. This marked increase in the CSF bioavailability was achieved without any distribution in the systemic circulation, demonstrating a direct and specific nose to brain delivery.

ObjectivesThis preclinical study was designed to compare gadolinium (Gd) brain uptake after repeated injections of a macrocyclic Gd-based contrast agent (GBCA) (gadoterate meglumine) or 2 linear GBCAs (L-GBCAs) (gadobenate dimeglumine or gadodiamide) on a translational model of moderate renal impair

New GABAB agonists, fluoropyridyl ether analogues of baclofen, have been synthesized as potential PET radiotracers. The compound with highest inhibition binding affinity as well as greatest agonist response, (R)-4-amino-3-(4-chloro-3-((2-fluoropyridin-4-yl)methoxy)phenyl)butanoic acid (1b), was radiolabeled with 18F with good radiochemical yield, high radiochemical purity, and high molar radioactivity. The regional brain distribution of the radiolabeled (R)-4-amino-3-(4-chloro-3-((2-[18F]fluoropyridin-4-yl)methoxy)phenyl)butanoic acid, [18F]1b, was studied in CD-1 male mice. The study demonstrated that [18F]1b enters the mouse brain (1% ID/g tissue). The accumulation of [18F]1b in the mouse brain was inhibited (35%) by preinjection of GABAB agonist 1a, suggesting that the radiotracer brain uptake is partially mediated by GABAB receptors. The presented data demonstrate a feasibility of imaging of GABAB receptors in rodents and justify further development of GABAB PET tracers with improved specific binding ...

Purpose of review To summarize recent advances pertaining to the mechanisms regulating brain docosahexaenoic acid (DHA) uptake. DHA is an omega-3 polyunsaturated fatty acid highly enriched in neuronal membranes and it is implicated in several important neurological processes. However, DHA synthesis is extremely limited within the brain. Recent findings There are two main plasma pools that supply the brain with DHA: the nonesterified pool and the lysophosphatidylcholine (lysoPtdCho) pool. Quantitatively, plasma nonesterified-DHA (NE-DHA) is the main contributor to brain DHA. Fatty acid transport protein 1 (FATP1) in addition to fatty acid-binding protein 5 (FABP5) are key players that regulate brain uptake of NE-DHA. However, the plasma half-life of lysoPtdCho-DHA and its brain partition coefficient are higher than those of NE-DHA after intravenous administration. Summary The mechanisms regulating brain DHA uptake are more complicated than once believed, but recent advances provide some clarity notably by suggesting that FATP1 and FABP5 are key contributors to cellular uptake of DHA at the blood-brain barrier. Elucidating how DHA enters the brain is important as we might be able to identify methods to better deliver DHA to the brain as a potential therapeutic.

This study sought to determine brain nicotine kinetics from use of the increasingly popular electronic cigarette (E-cig). Methods: In 17 E-cig users (9 men and 8 women), brain uptake of nicotine after inhalation from E-cigs was directly assessed using (11)C-nicotine PET. The brain nicotine kinetics were compared with those from smoking combustible cigarettes (C-cigs). Results: A single puff of E-cig vapor caused the nicotine concentration in the brain to rise quickly (mean time to reach 50% of maximum brain nicotine concentration, 27 s), with a peak amplitude 25% higher in women than men, resembling previous observations with C-cigs. Nonetheless, the accumulation from E-cigs (24%) was less than that from C-cigs (32%) in both men and women. Conclusion: E-cigs can deliver nicotine to the brain with a rapidity similar to that of C-cigs. Therefore, to the extent that rapid brain uptake promotes smoking reward, E-cigs might maintain a degree of nicotine dependence and also serve as a noncombustible substitute for cigarettes.

99mTc-oxiracetam was prepared. It can be used as a radiotracer for brain imaging. Under the optimum conditions (0.5 mg of oxiracetam, 50 μg of SnCl2·2H2O, pH 7, room temperature, 30 min), the radio-chemical yield determined by chromatographic methods reached 96%. Biodistribution studies with mice showed that the brain uptake of the complex was 5.1% injected dose per gram (% ID/g) at 5 min post injection. In this parameter, the complex surpasses the commercially available 99mTc-ECD (4.7% ID/g) and 99mTc-HMPAO (2.25% ID/g).

The search for non-invasive neural therapeutics is a problematic pursuit often hindered by the blood-brain barrier (BBB), a gatekeeper of endothelial cells and tight junctions closely regulating exchange between the bloodstream and brain tissue. A recent study of the complex [3-NO-3,3-κ 2 -(2,2′-N 2 C 10 H 6 (Me)((CH 2 ) 7 131 I)-4,4′)- closo -3,1,2-ReC 2 B 9 H 11 ] demonstrated its ability to not only safely pass through the BBB but also cleanly efflux out of neural tissue, suggesting potential use as a drug-delivery vehicle for central nervous system (CNS) delivery. However, due to the practical difficulty of asymmetric modification of the bipyridyl ligand, a more direct synthetic approach of carborane cage vertex adaptation has been investigated with the hope of utilizing such species for CNS therapeutics. A second prototype of [3,3-(CO) 2 -3-NO- closo -Re(8-O(CH 2 ) 2 O(CH 2 ) 2 125 I-3,1,2-C 2 B 9 H 10 )] was rapidly absorbed into the bloodstream from the subcutaneous site of injection and displayed a 1.1% Inj/g for peak brain uptake, which rapidly stabilized to 0.10% while the previous complex merely peaked at 0.10% Inj/g in initial studies. It was also determined that peak brain uptake of 15 mL/g was higher than lung and liver tissues, suggesting that the brain is somehow specifically targeted, although the exact rationale for selectivity remains to be explored.

To evaluate the efficacy of 18F-FC119S as a positron emission tomography (PET) radiopharmaceutical for the imaging of Alzheimer’s disease (AD), we studied the drug absorption characteristics and distribution of 18F-FC119S in normal mice. In addition, we evaluated the specificity of 18F-FC119S for β-amyloid (Aβ) in the AD group of an APP/PS1 mouse model and compared it with that in the wild-type (WT) group. The behavior of 18F-FC119S in the normal mice was characteristic of rapid brain uptake and washout patterns. In most organs, including the brain, 18F-FC119S reached its maximum concentration within 1 min and was excreted via the intestine. Brain PET imaging of 18F-FC119S showed highly specific binding of the molecule to Aβ in the cortex and hippocampus. The brain uptake and binding values for the AD group were higher than those for the WT group. These results indicated that 18F-FC119S would be a candidate PET imaging agent for targeting Aβ plaque.

Introduction There is an increasing demand for high throughput methods at early stages of preclinical radioligand development, in order to predict pharmacokinetic properties (e.g., biodistribution) and blood brain barrier (BBB) penetration. One of the most important physicochemical properties is the lipophilicity, measured by means of shake-flask (log P ) or HPLC methods. Yet, a plethora of experimental methods are described in the literature for the determination of logP values. These varying methods often lead to different results for one identical compound, which complicates any comparison or prediction for subsequent preclinical studies. However, a standardized and internationally applied and accepted database with log P values for a reliable comparison of the lipophilic character of radiotracers is still missing. Method Lipophilicity measurements were performed with 121 molecules using a high throughput HPLC method and Clog P values were calculated using ChemBioDraw®. Furthermore, log P measurements for six representative radiotracers were performed with the conventional shake-flask method and the results were statistically compared to the Clog P and HPLC log P results. Different log P thresholds, suggesting optimal BBB penetration according to literature, were selected and put into relation with the acquired HPLC log P and Clog P values of cerebral tracers. Results The results of the tested compounds ranged from −2.1 to 5.4 with the applied HPLC method. The acquired database comprises Clog P values of the whole set of compounds ranging from −4.11 to 6.12. Log P data from different methods were not comparable. The correlation of the obtained log P data to thresholds suggesting an optimal brain uptake resulted in a high number of false positive classifications. Conclusion The log P determination for prediction of BBB penetration is obsolete. The extensive database, including clinical relevant radiotracers, can be used as comparative set of values for preclinical studies, and serves as a basis for further critical discussions concerning the eligibility of log P .

The advent of dissolution dynamic nuclear polarization (DNP) led to the emergence of a new kind of magnetic resonance (MR) measurements providing the opportunity to probe metabolism in vivo in real time. It has been shown that, following the injection of hyperpolarized substrates prepared using dissolution DNP, specific metabolic bioprobes that can be used to differentiate between healthy and pathological tissue in preclinical and clinical studies can be readily detected by MR thanks to the tremendous signal enhancement. The present article aims at reviewing the studies of cerebral function and metabolism based on the use of hyperpolarized MR. The constraints and future opportunities that this technology could offer are discussed.

A suitable TSPO PET ligand may visualize and quantify neuroinflammation in a living brain. Herein we report a 18F-ligand, [18F]2 ([18F]FDPA), is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium ylide (SCIDY) strategy. [18F]2 demonstrated saturable specific binding to TSPO, substantially elevated brain uptake, and slow washout of bound PET signal in the preclinical models of brain neuroinflammation (cerebral ischemia and Alzheimer’s disease).

Nonspecific quantitation of [ 14 C]sucrose in blood and brain has been routinely used as a quantitative measure of the in vivo blood–brain barrier (BBB) integrity. However, the reported apparent brain uptake clearance ( K in ) of the marker varies widely (∼100-fold). We investigated the accuracy of the use of the marker in comparison with a stable isotope of sucrose ([ 13 C]sucrose) measured by a specific liquid chromatography–tandem mass spectrometry method. Rats received single doses of each marker, and the K in values were determined. Surprisingly, the K in value of [ 13 C]sucrose was 6- to 7-fold lower than that of [ 14 C]sucrose. Chromatographic fractionation after in vivo administration of [ 14 C]sucrose indicated that the majority of the brain content of radioactivity belonged to compounds other than the intact [ 14 C]sucrose. However, mechanistic studies failed to reveal any substantial metabolism of the marker. The octanol:water partition coefficient of [ 14 C]sucrose was >2-fold higher than that of [ 13 C]sucrose, indicating the presence of lipid-soluble impurities in the [ 14 C]sucrose solution. Our data indicate that [ 14 C]sucrose overestimates the true BBB permeability to sucrose. We suggest that specific quantitation of the stable isotope ( 13 C) of sucrose is a more accurate alternative to the current widespread use of the radioactive sucrose as a BBB marker.

Objective This Phase 2 study assessed the performance of positron emission tomography (PET) brain images made with Flutemetamol F 18 Injection in detecting β-amyloid neuritic plaques in Japanese subjects. Methods Seventy subjects (25 with probable Alzheimer’s disease (pAD), 20 with amnestic mild cognitive impairment (aMCI), and 25 cognitively normal healthy volunteers[HVs]) underwent PET brain imaging after intravenous Flutemetamol F 18 Injection (185 MBq). Images were interpreted as normal or abnormal for neuritic plaque density by each of five non-Japanese and five Japanese readers who were blinded to clinical data. The primary efficacy analysis (based on HV and pAD data) was the agreement of the non-Japanese readers’ image interpretations with the clinical diagnosis, resulting in estimates of positive percent agreement (PPA; based on AD subjects; similar to sensitivity) and negative percent agreement (NPA; based on HVs; similar to specificity). Secondary analyses included PPA and NPA for the Japanese readers; inter-reader agreement (IRA); intra-reader reproducibility (IRR); quantitative image interpretations (standardized uptake value ratios [SUVRs]) by diagnostic subgroup; test–retest variability in five pAD subjects; and safety. Results PPA was 92% for all non-Japanese readers and ranged from 88 to 92% for the Japanese readers. NPA ranged from 96 to 100% for both the non-Japanese readers and the Japanese readers. The majority image interpretations (the interpretations made independently by ≥3 of 5 readers) resulted in PPA values of 92 and 92% and NPA values of 100 and 96% for the non-Japanese and Japanese readers, respectively. IRA and IRR were strong. Composite SUVR values (mean of multiple regional values) allowed clear differentiation between pAD subjects and HVs. Test–retest variability ranged from 1.14 to 2.27%, and test–retest agreement of the blinded visual interpretations was 100% for all readers. Flutemetamol F 18 Injection was generally well tolerated. Conclusions The detection of brain neuritic plaques in Japanese subjects using [18F]Flutemetamol PET images gave results highly consistent with clinical diagnosis, with non-Japanese and Japanese readers giving similar results. Inter-reader agreement and intra-reader reproducibility were high for both sets of readers. Visual delineation of abnormal and normal scans was corroborated by quantitative assessment, with low test–retest variability. Trial registration Clinicaltrials.gov registration number NCT02813070. Electronic supplementary material The online version of this article (doi:10.1007/s12149-017-1154-7) contains supplementary material, which is available to authorized users.

18F-Labelling of aromatic moieties was limited to electron deficient aromatic systems for many years but recent developments have provided access to the direct labelling of electron rich aromatic systems. Herein we report the synthesis and 18F-labelling of iodonium ylide precursors in the pursuit of 18F-labelled 5-HT2A receptor agonist PET-ligands. Subsequent evaluation in pigs showed high brain uptake of the PET ligands but a blocking dose of ketanserin did not significantly reduce the signal in relevant brain regions - indicating that the ligands do not interact specifically with the 5-HT2A receptor in vivo.

BackgroundIn spite of the substantial therapeutic efficacy of triptans, their site of action is still debated. Subcutaneous sumatriptan is the most efficacious symptomatic treatment for cluster headache (CH) patients, showing therapeutic onset within a few minutes after injection even in migraine patients. However, whether subcutaneous sumatriptan is able to reach the CNS within this short time frame is currently unknown.MethodsHere, by means of liquid chromatography/mass spectrometry, we investigated peripheral and brain distribution of subcutaneous sumatriptan soon after injection in rats at a dose equivalent to that used in patients. Tissue sumatriptan contents were compared to those of oxazepam, a prototypical lipophilic, neuroactive drug.ResultsWe report that sumatriptan accumulated within brain regions of relevance to migraine and CH pathogenesis such as the hypothalamus and the brainstem as soon as 1 and 5 minutes after injection. Notably, sumatriptan brain distribution was faster than that of oxazepam, reaching concentrations exceeding its reported binding affinity for 5HT1B/Dreceptors, and in the range of those able to inhibit neurotransmitter release in vivo.ConclusionOur findings indicate that sumatriptan distributes within the CNS soon after injection, and are in line with prompt pain relief by parenteral sumatriptan in CH patients.

The combined use of different therapeutic agents in the treatment of neurodegenerative disorders is a promising strategy to halt the disease progression. In this context, we aimed to combine the anti-inflammatory properties of geraniol (GER) with the mitochondrial rescue effects of ursodeoxycholic acid (UDCA) in a newly-synthesized prodrug, GER-UDCA, a potential candidate against Parkinson's disease (PD). GER-UDCA was successfully synthetized and characterized in vitro for its ability to release the active compounds in physiological environments. Because of its very poor solubility, GER-UDCA was entrapped into both lipid (SLNs) and polymeric (NPs) nanoparticles in order to explore nose-to-brain pathway towards brain targeting. Both GER-UDCA nanocarriers displayed size below 200 nm, negative zeta potential and the ability to increase the aqueous dissolution rate of the prodrug. As SLNs exhibited the higher GER-UDCA dissolution rate, this formulation was selected for the in vivo GER-UDCA brain targeting experiments. The nasal administration of GER-UDCA-SLNs (1 mg/kg of GER-UDCA) allowed to detect the prodrug in rat cerebrospinal fluid (concentration range = 1.1 to 4.65 μg/mL, 30–150 min after the administration), but not in the bloodstream, thus suggesting the direct nose to brain delivery of the prodrug. Finally, histopathological evaluation demonstrated that, in contrast to the pure GER, nasal administration of GER-UDCA-SLNs did not damage the structural integrity of the nasal mucosa. In conclusion, the present data suggest that GER-UDCA-SLNs could provide an effective and non-invasive approach to boost the access of GER and UDCA to the brain with low dosages.

BACKGROUND Hepatopulmonary syndrome (HPS) is an arterial oxygenation defect induced by intrapulmonary vascular dilatation (IPVD) in the setting of liver disease and/or portal hypertension. This syndrome occurs most often in cirrhotic patients (4%–32%) and has been shown to be detrimental to functional status, quality of life, and survival. The diagnosis of HPS in the setting of liver disease and/or portal hypertension requires the demonstration of IPVD (i.e., diffuse or localized abnormally dilated pulmonary capillaries and pulmonary and pleural arteriovenous communications) and arterial oxygenation defects, preferably by contrast-enhanced echocardiography and measurement of the alveolar-arterial oxygen gradient, respectively. AIM To compare brain and whole-body uptake of technetium for diagnosing HPS. METHODS Sixty-nine patients with chronic liver disease and/or portal hypertension were prospectively included. Brain uptake and whole-body uptake were calculated using the geometric mean of technetium counts in the brain and lungs and in the entire body and lungs, respectively. RESULTS Thirty-two (46%) patients had IPVD as detected by contrast-enhanced echocardiography. The demographics and clinical characteristics of the patients with and without IPVD were not significantly different with the exception of the creatinine level (0.71 ± 0.18 mg/dL vs 0.83 ± 0.23 mg/dL; P = 0.041), alveolar-arterial oxygen gradient (23.2 ± 13.3 mmHg vs 16.4 ± 14.1 mmHg; P = 0.043), and arterial partial pressure of oxygen (81.0 ± 12.1 mmHg vs 90.1 ± 12.8 mmHg; P = 0.004). Whole-body uptake was significantly higher in patients with IPVD than in patients without IPVD (48.0% ± 6.1% vs 40.1% ± 8.1%; P = 0.001). The area under the curve of whole-body uptake for detecting IPVD was significantly higher than that of brain uptake (0.75 vs 0.54; P = 0.025). The optimal cut-off values of brain uptake and whole-body uptake for detecting IPVD were 5.7% and 42.5%, respectively, based on Youden’s index. The sensitivity, specificity, and accuracy of brain uptake > 5.7% and whole-body uptake > 42.5% for detecting IPVD were 23%, 89%, and 59% and 100%, 52%, and 74%, respectively. CONCLUSION Whole-body uptake is superior to brain uptake for diagnosing HPS.

The cause of antiseizure drug (ASD) resistance in epilepsy is poorly understood. Here, we focus on the transporter P-glycoprotein (P-gp) that is partly responsible for limited ASD brain uptake, which is thought to contribute to ASD resistance. We previously demonstrated that cyclooxygenase-2 (COX-2) and the prostaglandin E receptor, prostanoid E receptor subtype 1, are involved in seizure-mediated P-gp up-regulation. Thus, we hypothesized that inhibiting microsomal prostaglandin E(2) (PGE2) synthase-1 (mPGES-1), the enzyme generating PGE2, prevents blood-brain barrier P-gp up-regulation after status epilepticus (SE). To test our hypothesis, we exposed isolated brain capillaries to glutamate ex vivo and used a combined in vivo–ex vivo approach by isolating brain capillaries from humanized mPGES-1 mice to study P-gp levels. We demonstrate that glutamate signaling through the NMDA receptor, cytosolic phospholipase A2, COX-2, and mPGES-1 increases P-gp protein expression and transport activity levels. We show that mPGES-1 is expressed in human, rat, and mouse brain capillaries. We show that BI1029539, an mPGES-1 inhibitor, prevented up-regulation of P-gp expression and transport activity in capillaries exposed to glutamate and in capillaries from humanized mPGES-1 mice after SE. Our data provide key signaling steps underlying seizure-induced P-gp up-regulation and suggest that mPGES-1 inhibitors could potentially prevent P-gp up-regulation in epilepsy.—Soldner, E. L. B., Hartz, A. M. S., Akanuma, S.-I., Pekcec, A., Doods, H., Kryscio, R. J., Hosoya, K.-I., Bauer, B. Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier.