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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.

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 ...

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.

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.

The brain is the most important organ in our body requiring its unique microenvironment. By the virtue of its function, the blood-brain barrier poses a significant hurdle in drug delivery for the treatment of neurological diseases. There are also different theories regarding how molecules are typically effluxed from the brain. In this review, we comprehensively discuss how the different pharmacokinetic techniques used for measuring brain uptake/permeability of small molecules have evolved with time. We also discuss the advantages and disadvantages associated with these different techniques as well as the importance to utilize the right method to properly assess CNS exposure to drug molecules. Even though very strong advances have been made we still have a long way to go to ensure a reduction in failures in central nervous system drug development programs.

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.

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.

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.

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.

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.

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.

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.

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.

Numerous oral treatment options have been reported for neurological disorders, especially Alzheimer's disease (AD). Galantamine (GAL) is one of such drugs duly approved for management of AD. However, it exhibits poor brain penetration, low intestinal permeation and requires frequent dosing in AD treatment. The present studies, accordingly, were undertaken to develop DSPE-PEG 2000-based micelles loaded with GAL for efficient brain uptake, improved and extended pharmacokinetics, along with reduced dosing regimen.Mixed nanomicelles (MNMs) were systematically formulated using QbD approach, and characterized for morphology, entrapment efficiency andin vitrodrug release.Studies on CaCo-2 and neuronal U-87 cell lines exhibited substantial enhancement in the cellular permeability and uptake of the developed MNMs. Pharmacokinetic studies performed on rats showed significantly improved values of plasma AUC (i.e., 2.28-fold, p 0.001), ostensibly due to bypassing of hepatic first-pass metabolism and improved intestinal permeability, together with significant rise in MRT (2.08-fold, p 0.001) and tThe preclinical findings of the developed nanocarrier systems successfully demonstrate the notable potential of enhanced drug efficacy, extended duration of action and improved patient compliance.

Purpose: O-(2-[18F]fluoroethyl)-L-tyrosine (FET), a PET radiotracer of amino acid uptake, has shown potential for diagnosis and treatment planning in patients with glioblastoma (GBM). To improve quantitative assessment of FET PET imaging, we evaluated the repeatability of uptake of this tracer in patients with GBM. Methods: Test-retest FET PET imaging was performed on 8 patients with histologically confirmed GBM, who previously underwent surgical resection of the tumour. Data were acquired according to the protocol of a prospective clinical trial validating FET PET as a clinical tool in GBM. SUVmean, SUVmax and SUV98% metrics were extracted for both test and retest images and used to calculate 95% Bland-Altman limits of agreement (LoA) on lesion-level, as well as on volumes of varying sizes. Impact of healthy brain normalization on repeatability of lesion SUV metrics was evaluated. Results: Tumour LoA were [0.72, 1.46] for SUVmean and SUVtotal, [0.79,1.23] for SUVmax, and [0.80,1.18] for SUV98%. Healthy brain LoA were [0.80,1.25] for SUVmean, [0.80,1.25] for SUVmax, and [0.81,1.23] for SUV98%. Voxel-level SUV LoA were [0.76, 1.32] for tumour volumes and [0.80, 1.25] for healthy brain. When sampled over maximum volume, SUV LoA were [0.90,1.12] for tumour and [0.92,1.08] for healthy brain. Normalization of uptake using healthy brain volumes was found to improve repeatability, but not after normalization volume size of about 15 cm3. Conclusions Advances in Knowledge and Implications for Patient Care: Repeatability of FET PET is comparable to existing tracers such as FDG and FLT. Healthy brain uptake is slightly more repeatable than uptake of tumour volumes. Repeatability was found to increase with sampled volume. SUV normalization between scans using healthy brain uptake should be performed using volumes at least 15 cm3 in size to ensure best imaging repeatability.

Anti‐transferrin receptor (TfR)‐based bispecific antibodies have shown promise for boosting antibody uptake in the brain. Nevertheless, there are limited data on the molecular properties, including affinity required for successful development of TfR‐based therapeutics. A complex nonmonotonic relationship exists between affinity of the anti‐TfR arm and brain uptake at therapeutically relevant doses. However, the quantitative nature of this relationship and its translatability to humans is heretofore unexplored. Therefore, we developed a mechanistic pharmacokinetic‐pharmacodynamic (PK‐PD) model for bispecific anti‐TfR/BACE1 antibodies that accounts for antibody‐TfR interactions at the blood‐brain barrier (BBB) as well as the pharmacodynamic (PD) effect of anti‐BACE1 arm. The calibrated model correctly predicted the optimal anti‐TfR affinity required to maximize brain exposure of therapeutic antibodies in the cynomolgus monkey and was scaled to predict the optimal affinity of anti‐TfR bispecifics in humans. Thus, this model provides a framework for testing critical translational predictions for anti‐TfR bispecific antibodies, including choice of candidate molecule for clinical development.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, finding ways to increase drug delivery into the brain across the BBB remains a crucial challenge for researchers and clinicians in the field. Attempts have been made to boost brain uptake of enzymes by targeting various receptors (e.g., insulin and transferrin), and several other administration routes have also been tested. This review summarizes the available information on clinical trials (completed, ongoing, and planned) of novel therapeutic agents with efficacy against CNS symptoms in neuropathic MPS and also discusses the common associated challenges and pitfalls, some of which may help elucidate the pathogenesis of the neurodegeneration leading to the manifold CNS symptoms. A summary of current knowledge pertaining to the neuropathological progression and resultant neuropsychiatric manifestations is also provided, because it should be useful to ERT researchers looking for better approaches to treating CNS lesions in MPS.

Scope Docosahexaenoic acid (DHA, 22:6n-3) is crucial for optimal neuronal development and function, but the brain has a poor capacity to synthesize this fatty acid. When consumed acutely esterified to phosphatidylcholine, DHA is more efficient at targeting the brain than when consumed esterified to triacylglycerol. However, the brain DHA bioavailability of other forms of DHA-containing phospholipids, after oral ingestion, is unknown. The objective of this study is to compare brain uptake of DHA after acute gavage with different DHA carriers. Methods and results Ten-week-old rats were gavaged with 3 H-labeled DHA esterified to phosphatidylcholine (DHA-PtdCho), phosphatidylethanolamine (DHA-PtdEtn), phosphatidylserine (DHA-PtdSer) or triacylglycerol (DHA-TG). Six hours post-gavage, the animals were euthanized and radioactivity was quantified in the cortex and serum lipid classes. Radioactivity recovered in cortex total phospholipids was similar between the DHA-PtdCho and DHA-PtdSer groups and were 5.8 and 6.7 times higher than in the DHA-TG group, respectively. Serum total lipid radioactivity was higher in the DHA-PtdSer group than in the DHA-PtdCho and DHA-PtdEtn groups, but not compared to the DHA-TG group. Conclusion These results suggest that different mechanisms must be present to explain the serum and brain bioavailability differences between DHA-PtdCho and DHA-PtdSer, but these require further investigation.

Background: Birds comprise the most diverse group of terrestrial vertebrates. This success likely is related to the evolution of powered flight over 75 mya. Modern approaches for studying brain function, however, have yet to be fully adapted and applied to birds, especially as they relate to specific behaviors including flight. New method: We have developed a comprehensive set of in vivo experimental methods utilizing PET imaging with F-18 labeled fluorodeoxyglucose (FDG) to study regional changes in metabolism specifically related to flight, yet applicable to other behaviors as well. It incorporates approaches for selection of species, behavioral/imaging paradigm, animal preparation, radiotracer injection route, image quantification, and image analysis via an enhanced brain atlas. We also carried out preliminary modeling studies to better understand tracer kinetics. Results: The methods were successful in identifying brain regions statistically associated with flight using only 8 animals. Peak brain uptake of FDG between birds and rodents is similar despite much higher blood glucose levels in birds. We also confirmed that brain uptake of FDG steadily decreases after the initial peak and provide evidence that it may be related to greater dephosphorylation of FDG phosphate than that observed in mammals. Comparison with existing methods: FDG PET has been used in only a few studies of the bird brain. We introduce a new species, more realistic flight behavior, paired (test/retest) design, and improved quantification and analysis approaches. Conclusions: The proposed imaging protocol is non-invasive yet sensitive to regional metabolic changes in the bird brain related to behavior.

Compounds 1-14 were synthesized in a search for high-affinity CRF1 receptor ligands that could be radiolabeled with (11)C or (18)F for use as positron emission tomography (PET) radiotracers. Derivatives of 2 were developed which contained amide N-fluoroalkyl substituents. Compounds [(18)F]24 and [(18)F]25 were found to have appropriate lipophilicities of logP7.4=2.2 but microPET imaging with [(18)F]25 demonstrated limited brain uptake.

A new series of fluoro-pegylated benzyloxybenzenes were designed, synthesized and evaluated as PET probes for early detection of Aβ plaques. Molecular docking revealed that all of the flexible benzyloxybenzenes inserted themselves into the hydrophobic Val18_Phe20 cleft on the flat spine of the Aβ fiber, in a manner similar to that of IMPY molecule. The most potent probe, [(18)F]9a, exhibited a combination of high binding affinity to Aβ aggregates (Ki = 21.0 ± 4.9 nM), high initial brain uptake (9.14% ID/g at 2 min), fast clearance from normal brain tissue (1.79% ID/g at 60 min), and satisfactory in vivo biostability in the brain (95% of intact form at 2 min). [(18)F]9a clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [(18)F]9a did penetrate the intact BBB and specifically bind to Aβ plaques in vivo. Overall, [(18)F]9a may be a potential PET probe for imaging Aβ plaques in AD brains.

DB213 is an HIV-1 replication inhibitor targeting the Central Nervous System for the treatment of HIV-associated neurocognitive disorders. Current study aims to develop an in situ thermosensitive gelling system for intranasal delivery of DB213 facilitated by Statistical Design of Experiment (DoE) to conduct a more efficient experimentation by extracting the maximum amount of information from limited experiments. In our current study, information was extracted from twenty-five experimental designs from MODDE® Software and a mathematical model was successfully developed to predict formulations to achieve desired performance as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, Chitosan, DB213 and the performances of in situ thermosensitive gels. Based on DoE, in situ thermosensitive gels of 1% DB213 (F1) and 5% DB213 (F2) were developed for further in vivo bioavailability and brain uptake evaluations in Sprague-Dawley rats and C57BL/6 mice, respectively. In comparison to DB213 water solution, intranasal administrations of F1 at 1 mg/kg in rats and F2 at 25 mg/kg in mice demonstrated relative bioavailabilities of 145% and 165% with significant increase in brain uptake.

Introduction Phosphodiesterase 10A (PDE10A) is a member of the PDE enzyme family that degrades cyclic adenosine and guanosine monophosphates (cAMP and cGMP). Based on the successful development of [ 11 C]T-773 as PDE10A positron emission tomography (PET) radioligand, in this study our aim was to develop and evaluate fluorine-18 analogs of [ 11 C]T-773. Methods [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 were synthesized from the same precursor used for 11 C-labeling of T-773 in a two-step approach via 18 F-fluoromethylation and 18 F-fluoroethylation, respectively, using corresponding deuterated synthons. A total of 12 PET measurements were performed in seven non-human primates. First, baseline PET measurements were performed using High Resolution Research Tomograph system with both [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 ; the uptake in whole brain and separate brain regions, as well as the specific binding and tissue ratio between putamen and cerebellum, was examined. Second, baseline and pretreatment PET measurements using MP-10 as the blocker were performed for [ 18 F]FM-T-773-d 2 including arterial blood sampling with radiometabolite analysis in four NHPs. Results Both [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 were successfully radiolabeled with an average molar activity of 293 ± 114 GBq/μmol (n=8) for [ 18 F]FM-T-773-d 2 and 209 ± 26 GBq/μmol (n=4) for [ 18 F]FE-T-773-d 4 , and a radiochemical yield of 10% (EOB, n=12, range 3%–16%). Both radioligands displayed high brain uptake (~5.5% of injected radioactivity for [ 18 F]FM-T-773-d 2 and ~3.5% for [ 18 F]FE-T-773-d 4 at the peak) and a fast washout. Specific binding reached maximum within 30 min for [ 18 F]FM-T-773-d 2 and after approximately 45 min for [ 18 F]FE-T-773-d 4 . [ 18 F]FM-T-773-d 2 data fitted well with kinetic compartment models. BP ND values obtained indirectly through compartment models were correlated well with those obtained by SRTM. BP ND calculated with SRTM was 1.0–1.7 in the putamen. The occupancy with 1.8 mg/kg of MP-10 was approximately 60%. Conclusions [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 were developed as fluorine-18 PET radioligands for PDE10A, with the [ 18 F]FM-T-773-d 2 being the more promising PET radioligand warranting further evaluation.

Background Increased brain uptake on [18F]AV45 PET is a biomarker for Alzheimers disease (AD). The standardised uptake value ratio (SUVR) is widely used for quantification but is subject to variability. Here we evaluate how SUVR of a cortical target region is affected by blood flow changes in the target and two frequently used reference regions. Methods Regional baseline time-activity curves (TACs) were simulated based on metabolite-corrected plasma input functions and pharmacokinetic parameters obtained from our previously acquired data in healthy control (HC; n = 10), amnestic mild cognitive impairment (aMCI; n = 15) and AD cohorts (n = 9). Blood flow changes were simulated by altering the regional tracer delivery rate K1 (and clearance rate k2) between -40% and +40% from its regional baseline value in the target region and/or cerebellar grey (CB) or subcortical white matter (WM) reference regions. The corresponding change in SUVR was calculated at 5060 min post-injection. Results A -40% blood flow reduction in the target resulted in an increased SUVRtarget (e.g. SUVRprecuneus: +10.0±5% in HC, +2.5±2% in AD), irrespective of the used reference region. A -40% blood flow reduction in the WM reference region increased SUVRWM (+11.5±4% in HC, +13.5±3% in AD) while a blood flow reduction in CB decreased SUVRCB (-9.5±6% in HC, -5.5±2% in AD), irrespective of the used target region. A -40% flow reduction in both the precuneus and reference WM (i.e., global flow change) induced an increased SUVR (+22.5±8% in HC, +16.0±4% in AD). When considering reference CB instead, SUVR was decreased by less than -5% (both in HC and AD). Conclusion Blood flow changes introduce alterations in [18F]AV45 PET SUVR. Flow reductions in the CB and WM reference regions resulted in a decreased and increased SUVR of the target, respectively. SUVR was more affected by global blood flow changes when considering WM instead of CB normalization.

Central nervous system disorders are already prevalent and steadily increasing among populations worldwide. However, most of the pharmaceuticals present on world markets are ineffective in treating cerebral diseases, because they cannot effectively cross the blood brain barrier (BBB). Solid lipid nanoparticles (SLN) are nanospheres made from biocompatible solid lipids, with unique advantages among drug carriers: they can be used as vehicles to cross the BBB. This review examines the main aspects surrounding brain delivery with SLN, and illustrates the principal mechanisms used to enhance brain uptake of the delivered drug.

Vortioxetine is a new multi-modal drug against major depressive disorder with high affinity for a range of different serotonergic targets in the CNS. We report the (11)C-labeling of vortioxetine with [(11)C]MeI using a Suzuki-protocol that allows for the presence of an unprotected amine. Preliminary evaluation of [(11)C]vortioxetine in a Danish Landrace pig showed rapid brain uptake and brain distribution in accordance with the pharmacological profile, all though an unexpected high binding in cerebellum was also observed. [(11)C]vortioxetine displayed slow tracer kinetics with peak uptake after 60 min and with limited wash-out from the brain. Further studies are needed but this radioligand may prove to be a valuable tool in unraveling the clinical effects of vortioxetine.

O -Desmethylvenlafaxine (desvenlafaxine, ODV) is a recently approved antidepressant which in some clinical studies failed to meet a satisfactory end-point. The aim of this study was to prepare a series of phenolic esters of ODV and evaluate their potential as ODV prodrugs with improved brain uptake. Fifteen phenolic esters (compounds 1a – o) were synthesized and their pharmacokinetic profiles evaluated in rat. The four compounds producing the highest relative bioavailability of ODV in rat (compounds 1c , 1e , 1n , 1o ) were then studied to evaluate their brain uptake. Of these four compounds, compound 1n (the piperonylic acid ester of ODV) demonstrated the highest C max of ODV both in the rat hypothalamus and total brain. Finally the pharmacokinetics of 1n were evaluated in beagle dog where the increase in relative bioavailability of ODV was found to be as great as in rat. This high relative bioavailability of ODV coupled with its good brain penetration make 1n the most promising candidate for development as an ODV prodrug.

A radiolabeled PET! A (11) C-labeled derivative of N,N'-(methylenedi-4,1-phenylene)bis[2-(1-pyrrolidinyl) acetamide] (GN8), an antiprion agent currently under development, was synthesized by palladium-catalyzed rapid methylation of aryltributylstannane and assessed for brain penetration and organ distribution in rats by positron emission tomography (PET).