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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).

Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.

Development of drug delivery systems for brain delivery is one of the most challenging research topics in pharmaceutical areas, mainly due to the presence of the blood-brain barrier (BBB), which separates the blood from the cerebral parenchyma thus limiting the brain uptake of the majority of therapeutic agents. Among the several carriers, which have been studied to overcome this problem, liposomes have gained increasing attention as promising strategies for brain-targeted drug delivery. The most advantageous features of liposomes are their ability to incorporate and deliver large amounts of drug and the possibility to decorate their surface with different ligands.The purpose of this review is to explore the different approaches studied to transport and deliver therapeutics and imaging agents to the brain by using liposomes. In the first part of the review, particular attention is paid to describe the anatomy of the BBB and different physiological transport mechanisms available for drug permeation. In the second part, the different strategies for the delivery of a drug to the brain using liposomes are reviewed for each transport mechanism.Over the last decade, there have been significant developments concerning liposomal brain delivery systems conjugated with selected ligands with high specificity and low immunogenicity. An universally useful liposomal formulation for brain targeting does not exist but liposome design must be modulated by the appropriate choice of the specific homing device and transport mechanism.

Drug delivery to the brain is impeded by the blood-brain barrier (BBB). Here, we attempted to enhance the brain uptake of cationic dopamine by utilizing the large amino acid transporter 1 (LAT1) at the BBB by prodrug approach.Three amino acid prodrugs of dopamine were synthesized and their prodrug properties were examined in vitro. Their LAT1-binding and BBB-permeation were studied using the in situ rat brain perfusion technique. The brain uptake after intravenous administration and the dopamine-releasing ability in the rat striatum after intraperitoneal administration were also determined for the most promising prodrug.All prodrugs underwent adequate cleavage in rat tissue homogenates. The prodrug with phenylalanine derivative as the promoiety had both higher affinity for LAT1 and better brain uptake properties than those with an alkyl amino acid - mimicking promoiety. The phenylalanine prodrug was taken up into the brain after intravenous injection but after intraperitoneal injection the prodrug did not elevate striatal dopamine concentrations above those achieved by corresponding L-dopa treatment.These results indicate that attachment of phenylalanine to a cationic drug via an amide bond from the meta-position of its aromatic ring could be highly applicable in prodrug design for LAT1-mediated CNS-delivery of not only anionic but also cationic polar drugs.

The bromodomain and extraterminal domain (BET) inhibitors have been extensively studied for tumor treatment in the past few years. Recently, BET-containing proteins have been reported to play a key role in brain functions, such as learning and memory. BET proteins have also been shown to be a potential therapeutic target for substance abuse disorders. Development of a molecular probe for noninvasive imaging will elucidate the distribution and functional roles of BET in the living subject and accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and pilot imaging of a novel BET imaging agent, [11C]MS417. Our imaging results demonstrate that this probe has moderate brain uptake, good specificity, good selectivity, and appropriate kinetics and distribution. [11C]MS417 is an ideal lead compound for further optimization of clinical BET PET radiotracer tools and MS417 could be used as a blood-brain-barrier-penetrant compound for preclinical research.

An effective separation and simultaneous determination of corynoxeine and its metabolites using high-performance liquid chromatography with tandem mass spectrometry was developed and validated. The method was applied to pharmacokinetics and in vivo distribution investigations in rats after oral (0.105 mmol kg(-1)) and intravenous (0.0105 mmol kg(-1)) doses of corynoxeine. Its brain uptake index was of 3.08 × 10(-11) mol g(-1) at 3 h and 3.75 × 10(-11) mol g(-1) at 74 min after oral and intravenous doses, respectively.

Introduction: In this study, the influence of physiological determinants on 18F-fluoro-d-glucose (18F-FDG) brain uptake was evaluated in a mouse model of Alzheimer disease. Materials and Methods: TASTPM (Tg) and age-matched C57BL/6 J (WT) mice were fasted for 10 hours, while another group was fasted for 20 hours to evaluate the effect of fasting duration. The effect of repeatedly scanning was evaluated by scanning Tg and WT mice at days 1, 4, and 7. Brain 18F-FDG uptake was evaluated in the thalamus being the most indicative region. Finally, the cerebellum was tested as a reference region for the relative standard uptake value (rSUV). Results: When correcting the brain uptake for glucose, the effect of different fasting durations was attenuated and the anticipated hypometabolism in Tg mice was demonstrated. Also, with repeated scanning, the brain uptake values within a group and the hypometabolism of the Tg mice only remained stable over time when glucose correction was applied. Finally, hypometabolism was also observed in the cerebellum, yielding artificially higher rSUV values for Tg mice. Conclusion: Corrections for blood glucose levels have to be applied when semiquantifying 18F-FDG brain uptake in mouse models for AD. Potential reference regions for normalization should be thoroughly investigated to ensure that they are not pathologically affected also by afferent connections.

Three novel (18)F-labeled 4-aminoquinazoline derivatives, N-(3-chloro-4-fluorophenyl)-6-(2-[(18)F]fluoroethoxy)-7-methoxyquinazolin-4-amine([(18)F]1), N-(3-ethynylphenyl)-6-(2-[(18)F]fluoroethoxy)-7-methoxyquinazolin-4-amine([(18)F]2), and N-(3-bromophenyl)-6-(2-[(18)F]fluoroethoxy)-7-methoxyquinazolin-4-amine([(18)F]3) were synthesized and radiolabeled by two-step reaction with overall radiochemical yield of 21-24% (without decay corrected). Then we carried out their biodistribution experiments in S180 tumor-bearing mice. Results showed that they had certain concentration accumulation in tumor and fast clearance from muscle and blood. It was encouraging that [(18)F]3 was competitive among three (18)F-labeled 4-aminoquinazoline derivatives in some aspects such as tumor/muscle uptake ratio reaching 7.70 at 60 min post-injection, tumor/blood uptake ratio reaching 6.61 at 120 min post-injection. So we compared radioactivity characteristics of [(18)F]3 with those of [(18)F]-FDG and L-[(18)F]-FET in the same animal model. The absolute radioactivity uptake of [(18)F]3 in tumor reached 3.31 at 60 min p.i., which was slightly higher than [(18)F]-FDG (2.16) and L-[(18)F]-FET (2.75) at the same time phase. For [(18)F]3, tumor/muscle uptake ratio peaked 7.70 at 60 min, which was obviously superior to those of [(18)F]-FDG and L-[(18)F]-FET at all time points. The tumor/brain uptake ratios of [(18)F]3 were 10.36, 17.42, 41.11 at 30 min, 60 min and 120 min post-injection, respectively, and are much higher than those of L-[(18)F] FET (2.54, 2.92 and 2.95) and [(18)F]-FDG (0.61, 1.02 and 1.33) at the same time points. All these results indicate that [(18)F]3 is promising to become a potential PET tumor imaging agent.

We report the synthesis and biological evaluation of novel (E)-5-styryl-1H-indole and (E)-6-styrylquinoline derivatives as probes for imaging β-amyloid (Aβ) plaques. These derivatives showed binding affinities for Aβ₁₋₄₀ aggregates with K(i) values varying from 4.1 to 288.4 nM. (E)-5-(4-iodostyryl)-1H-indole (8) clearly stained Aβ plaques in the brain sections of Alzheimer's disease (AD) model mice (APP/PS1). Furthermore, autoradiography for [¹²⁵I]8 displayed intense and specific labeling of Aβ plaques in the brain sections mentioned above with low background. In biodistribution experiments using normal mice [¹²⁵I]8 showed high initial brain uptake followed by rapid washout (4.27 and 0.64% ID/g at 2 and 30 min post injection, respectively). These findings suggests that [¹²³I]8 may be a potential SPECT imaging agent for detecting Aβ plaques in AD brain.

In the present study, a styryltriazole and four resveratrol derivatives were synthesized as candidates for β-amyloid (Aβ) plaque imaging. On the basis of their binding affinities to Aβ(1–42) aggregates, the styryltriazole (1, Ki = 12.8 nM) and one resveratrol derivative (5, Ki = 0.49 nM) were labeled with 18F. In normal mice, tissue distribution of [18F]5 showed good initial brain uptake (3.26% ID/g at 2 min) but slow wash-out from brains (2-to-60 min uptake ratio: 2.9). Furthermore, it underwent in vivo metabolic defluorination (1.88% ID/g at 2 min and 9.73% ID/g at 60 min). In contrast, [18F]1 displayed high initial brain uptake (5.38% ID/g at 2 min) with rapid wash-out from brains (0.52% ID/g at 60 min; 2-to-60 min uptake ratio: 10.3). These results indicate that [18F]1 has in vivo kinetics comparable to PET radiopharmaceuticals currently under commercial development, demonstrating that [18F]1 is a desirable PET radioligand for Aβ plaque imaging.

A major component in the protection of the brain against blood-borne toxic influences is the multispecific efflux pump P-glycoprotein. This pump, a 170 kD protein, located at the luminal side of the capillary endothelial cells, has a large capacity and is capable of extruding a wide array of structurally divergent substrates. The brain uptake of the majority of antidepressants and antipsychotics, as well as many other psychotropic drugs and endogenous compounds is hampered by the activity of P-glycoprotein. In this review we discuss the current state of knowledge concerning the role of Pglycoprotein on pharmacokinetics of psychiatric drugs and the impact of modulation of P-glycoprotein on major psychiatric disorders. Relevant issues in reference to the function of P-glycoprotein and other efflux pumps in the blood-brain barrier related to mood disorders and schizophrenia are addressed, such as a possible role of P-glycoprotein as a susceptibility factor in depressive disorders and psychotic disorders.

Advances in the field of shuttle-mediated drug delivery have been made in the last decade; however, the treatment of brain disorders still remains a great challenge because of the presence of the blood-brain barrier (BBB), a structure that limits the access of drugs to their site of action in the central nervous system. Several strategies have been proposed to enhance the transport of drugs across the BBB. In this Review, we focus on the vector-mediated approach, in which a drug is coupled to a molecule (shuttle) that has the ability to cross the BBB and deliver the drug to the brain.

P-glycoprotein (P-gp) plays a pivotal role in limiting the penetration of xenobiotic compounds into the brain at the blood–brain barrier (BBB), where its expression increases with maturation in rats. We investigated developmental changes in P-gp function in the BBB of nonhuman primates using PET with R-11C-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of 11C-oseltamivir, a substrate for P-gp, was investigated as practical examples. Methods: PET studies in infant (age, 9 mo), adolescent (age, 24–27 mo), and adult (age, 5.6–6.6 y) rhesus monkeys (Macaca mulatta) were performed with R-11C-verapamil and also with 11C-oseltamivir. Arterial blood samples and PET images were obtained at frequent intervals up to 60 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots using data collected within the first 2.5 min after tracer administration. Results:R-11C-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-11C-verapamil decreased rapidly in all subjects. The maximum brain uptake in infant (0.033% ± 0.007% dose/g of brain) and adolescent (0.020% ± 0.002% dose/g) monkeys was 4.1- and 2.5-fold greater, respectively, than uptake in adults (0.0082% ± 0.0007% dose/g). The clearance of brain R-11C-verapamil uptake in adult monkeys was 0.056 ± 0.010 mL/min/g, significantly lower than that in infants (0.11 ± 0.04 mL/min/g) and adolescents (0.075 ± 0.023 mL/min/g). 11C-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-11C-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightly lower than that in infant (0.0097 and 0.0104 mL/min/g) and adolescent (0.0097 and 0.0098 mL/min/g) monkeys. Conclusion: These results suggest that P-gp function in the BBB changes with development in rhesus monkeys, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.

We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral β-amyloid (Aβ) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Aβ. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Aβ(1-40) (K(i) = 3.5 nM) and Aβ(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aβ-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aβ plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of Aβ plaques.

Background/Aims: The serotonergic system, especially the 5-HT2A receptor, is involved in various diseases and conditions. We have recently developed a new [18F]-5-HT2A receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [18F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT2A receptors in vivo. However, [18F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier, thus limiting its availability in the central nervous system. The aim of this study was to determine whether transport by P-gp influences the distribution ratio of [18F]MH.MZ in the frontal cortex. Methods: The approach was based on P-gp knockout mice which were compared with wild-type mice under several conditions. In vivo pharmacokinetic and microPET investigations were carried out. Results: All analyses showed that [18F]MH.MZ entered the brain and was sensitive to P-gp transport. In P-gp knockout mice, brain concentrations of MH.MZ were about 5-fold higher than in wild-type animals which is reflected by a 2-fold increase in standardized uptake values of [18F]MH.MZ in the frontal cortex of P-gp knockout mice. Conclusion: Our results give evidence for a functional role of transport mechanisms at the blood-brain barrier, specifically of P-gp, and its subregional distribution. Investigation of these mechanisms will benefit the development of more efficient radioligands and drugs for molecular imaging and pharmacotherapy of the mentally ill.

2-Deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT) is becoming increasingly available as an imaging modality in veterinary medicine. The purpose of this study was to report semiquantitative standard uptake values (SUV) of malignant and nonmalignant tissues and organs in canine cancer patients. FDG PET/CT was performed in 14 dogs including, nine mesenchymal tumors, four carcinomas, and one incompletely excised mast cell tumor. A generally higher FDG uptake was observed in carcinomas relative to sarcomas. Maximum SUV of carcinomas ranged from 7.6 to 27.0, and for sarcomas from 2.0 to 10.6. The FDG SUV of several organs and tissues, including regional brain uptake is reported, to serve as a reference for future FDG PET studies in canine cancer patients. Several potential pitfalls have been recognized in interpretation of FDG PET images of human patients, a number of these were also observed in this study.

The blood-brain barrier (BBB) controls the entry of xenobiotics into the brain. Often the development of central nervous system drugs needs to be terminated because of their poor brain uptake. We describe a way to achieve large neutral amino acid transporter (LAT1)-mediated drug transport into the rat brain. We conjugated ketoprofen to an amino acid l-lysine so that the prodrug could access LAT1. The LAT1-mediated brain uptake of the prodrug was demonstrated with in situ rat brain perfusion technique. The ability of the prodrug to deliver ketoprofen into the site of action, the brain intracellular fluid, was determined combining in vivo and in vitro experiments. A rapid brain uptake from blood and cell uptake was seen both in in situ and in vivo experiments. Therefore, our results show that a prodrug approach can achieve uptake of drugs via LAT1 into the brain intracellular fluid. The distribution of the prodrug in the brain parenchyma and the site of parent drug release in the brain were shown with in vivo and in vitro studies. In addition, our results show that although lysine or ketoprofen are not LAT1-substrates themselves, by combining these molecules, the formed prodrug has affinity for LAT1.

Faint brain [(18)F]fluoro-2-deoxyglucose (FDG) uptake has sporadically been reported in patients with FDG-avid large or diffusely extended tumors. The purpose of this study was to investigate whether there is a correlation between massive tumor uptake and decreased brain uptake on FDG positron emission tomography/computed tomography (PET/CT).Sixty-five patients with histologically confirmed non-Hodgkin's lymphoma who underwent FDG-PET/CT were enrolled. Thirty control subjects were also included to evaluate normal brain FDG uptake. PET/CT examinations were retrospectively reviewed. The volumetric regions of interest were placed over lesions by referring to CT and PET/CT fusion images to measure mean standardized uptake value (SUVavg). The products of SUVavg and tumor volume were calculated as total glycolytic volume (TGV). The maximum SUV (SUVmax) and SUVavg were measured in the cerebrum and cerebellum. The values of TGV and brain FDG uptake were plotted and analyzed with a linear regression method.In the lymphoma patients, there were statistically significant negative correlations between TGV and brain SUVs.Demonstrating a significant negative correlation between TGV and brain uptake validated the phenomenon of decreased brain FDG uptake. Diversion of FDG from the brain to the lymphoma tissue may occur during the FDG accumulation process. Recognition of this phenomenon prevents unnecessary further neurological examinations in such cases.

This report presents that Deferiprone, the only clinically used 3-hydroxypyridin-4-one (HPO), is able to penetrate the blood-brain barrier (BBB) in guinea pigs, whereas its glucosylated analogue is unable to do so. This finding is contrary to published information suggesting that the glucosylation of HPOs is a viable means of enhancing the brain uptake of this group of compounds.

This article reported the synthesis and bioevaluation of two [(18)F] labeled benzimidazole derivatives, 4-(5-(2-[(18)F] fluoro-4-nitrobenzamido)-1-methyl-1H-benzimidazol-2-yl) butanoic acid ([(18)F] FNBMBBA, [(18)F]a1) and 3-(2-fluoroethyl)-7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid ([(18)F] FEMPBBA, [(18)F]b1) for PET tumor imaging. The preparation [(18)F] FEMPBBA was completed in 1h with overall radiochemical yield of 50-60% (without decay corrected). Biodistribution assay in S180 tumor bearing mice of both compounds were carried out, and the results are both meaningful. [(18)F] FEMPBBA which can be taken as a revision of [(18)F] FNBMBBA got an excellent result, and has significant advantages in some aspects compared with L-[(18)F] FET and [(18)F]-FDG in the same animal model, especially in tumor/brain uptake ratio. The tumor/brain uptake ratio of [(18)F] FEMPBBA gets to 4.81, 7.15, and 9.8 at 30min, 60min and 120min, and is much higher than that of L-[(18)F] FET (2.54, 2.92 and 2.95) and [(18)F]-FDG (0.61, 1.02, 1.33) at the same time point. The tumor/muscle and tumor/blood uptake ratio of [(18)F] FEMPBBA is also higher than that of L-[(18)F] FET at 30min and 60min. This result indicates compound [(18)F] FEMPBBA is a promising radiotracer for PET tumor imaging.

Two novel triaryl ligands 2 and 5 with potent in vitro binding affinities for the cannabinoid subtype-2 (CB2) receptor were labeled with a positron-emitting radioactive nuclide (11)C. Radioligands [(11)C]2, [(11)C]5, and their analogs [(11)C]3 and [(11)C]4 were synthesized by O-[(11)C]methylation of their corresponding phenol precursors with [(11)C]CH(3)I. [(11)C]2-5 had relatively high uptakes (>1.2% injected dose/g tissue) in mouse brains.

Previous studies have infused radiolabeled arachidonic acid (AA) into rat brains and followed AA esterification into phospholipids for up to 24 h; however, the half-life of AA in rat brain phospholipids is unknown. Eighteen day old rats were fed either an n-3 PUFA adequate or deprived diet for 15 weeks. Following the 15 weeks, 40 microCi of [(3)H] AA was injected intracerebroventricularly into the right lateral ventricle using stereotaxic surgery and returned to their dietary treatment. From 4-120 days after [(3)H] AA administration, brains were collected for chemical analyses. The half-life of AA in rat brain phospholipids was 44 +/- 4 days for the n-3 PUFA adequate group and 46 +/- 4 days for the n-3 PUFA deprived group, which closely approximates the predicted half-life previously reported, based on the rate of entry from the plasma unesterified pool, suggesting the plasma unesterified pool is a major contributor to brain uptake of AA. Furthermore, unlike a previous report in which the half-life of brain phospholipid docosahexaenoic acid (DHA) was increased in n-3 PUFA deprived rats, n-3 PUFA deprivation did not significantly alter the AA half-life, suggesting different mechanisms exist to maintain brain concentrations of AA and DHA.

This study reports the synthesis and characterization of N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl-4-[(18)F]fluorobenzamide ([(18)F]MPP3F). The total reaction time for [(18)F]MPP3F, including final high-performance liquid chromatography purification, was about 3h. Typical decay-corrected radiochemical yield was 18.4+/-3.1%. The radiochemical purity was98%. Biodistribution in mice showed that [(18)F]MPP3F is a potential brain imaging agent for positron emission tomography. The brain uptake of [(18)F]MPP3F was 6.59+/-0.77% Injected Dose/g at 2 min post-injection time. A brain-to-blood ratio of 3.67 was reached at 15 min after injection.

We evaluated the usefulness of small animal brain positron emission tomography (PET) imaging with the amyloid-beta (A beta) probe 2-(1-{6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malonitrile ([(18)F]FDDNP) and with 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) for detection and quantification of pathological changes occurring in a transgenic mouse model of Alzheimer's disease (Tg2576 mice).[(18)F]FDDNP (n = 6) and FDG-PET scans (n = 3) were recorded in Tg2576 mice (age 13-15 months) and age-matched wild-type litter mates. Brain volumes of interest were defined by co-registration of PET images with a 3D MOBY digital mouse phantom. Regional [(18)F]FDDNP retention in mouse brain was quantified in terms of the relative distribution volume (DVR) using Logan's graphical analysis with cerebellum as a reference region.Except for a lower maximum brain uptake of radioactivity in transgenic animals, the regional brain kinetics as well as DVR values of [(18)F]FDDNP appeared to be similar in both groups of animals. Also for FDG, regional radioactivity retention was almost identical in the brains of transgenic and control animals.We could not detect regionally increased [(18)F]FDDNP binding and regionally decreased FDG binding in the brains of Tg2576 transgenic versus wild-type mice. However, small group differences in signal might have been masked by inter-animal variability. In addition, technical limitations of the applied method (partial volume effect, spatial resolution) for measurements in such small organs as mouse brain have to be taken into consideration.