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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.

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.

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.

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).

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.

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.

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon-11 (C-11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium-substituted [11C]clorgyline ([11C]clorgyline-D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline-D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C-11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline-D2. Thus deuterium-substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non-MAO A binding which is most apparent in the white matter. The characterization of the non-MAO A binding component of this widely used MAO A inhibitor merits further investigation.

Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are, thereby, biomarkers of cellular inflammation in brain. We recently developed two PET ligands with an aryloxyanilide structure to image PBRs and now evaluate the kinetics of these radiotracers in monkey to determine whether they are suitable to explore in human. Baseline and receptor-blocking scans were performed with [(11)C]PBR01 and [(18)F]PBR06 in conjunction with serial measurements of the arterial plasma concentration of parent radiotracer separated from radiometabolite. We used brain and plasma data with compartmental modeling to calculate regional brain distribution volume, which is equal to the ratio at equilibrium of the concentration of radioligand in brain to that of plasma. The distribution volume of [(11)C]PBR01 was inaccurately estimated in the baseline scans, possibly because of the short half-life of (11)C or the presence of radiometabolite in brain. In contrast, the distribution volume of [(18)F]PBR06 was stably determined within 200 min of scanning, and nondisplaceable uptake was only approximately 10% of total brain uptake. [(18)F]PBR06 is promising for use in human because brain activity could be quantified with standard compartmental models and showed higher ratios ( approximately 10:1) of specific to nonspecific uptake. A critical factor for human use will be whether the tracer has adequately fast wash out from brain relative to the half-life of the radionuclide to obtain stable values of distribution volume.

Brain uptake of 3H endogenous nucleosides in rats was measured by Brain Uptake Index method, using 14C-sucrose as a referent molecule. The values obtained in control group were 4.68±0.93 for adenosine, 4.10±0.72 for guanosine and 1.14±0.72 for thymidine, indicating significant blood-to-brain transport of purine nucleosides. NO-synthase inhibition was induced by i.p. application of 25 mg/kg 1-ω-nitro-arginin methyl ester (L-NAME) and 5mg/kg diphenylethiodonium (brain parenchyma NOS inhibitor). HPLC analysis showed that the concentration of L-NAME in brain was sufficient to cause inhibition of NOS. Application of L-NAME resulted in significant inhibition of brain uptake for both purine nucleosides. Unlike adenosine, in the case of guanosine a correlation between the rate of brain uptake inhibition and the L-NAME concentration in plasma, but not in brain, was obtained. Application of diphenylethiodonium also caused a significant decrease in both guanosine and adenosine brain uptake. The obtained results were not significantly different from the BUI values obtained after preapllication of L-NAME. Our results suggest that NOS inhibition decreases brain uptake of purine nucleosides. Such effect(s) are probably due to the inhibition of brain parenchyma NOS.

As a possible lipophilic spin probe of in vivo electron spin resonance (ESR), 3-methoxy carbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-yloxy (MCPROXYL) was examined. The permeability of the blood-brain barrier to this compound was evaluated with a brain uptake index and autoradiography, with result that this probe is well distributed in the brain. The in vivo ESR spectra were measured in the head and the abdomen of MCPROXYL-injected living mice. The rate of signal decay of MCPROXYL in the head measured at one hour after X-irradiation was about 75% of that of the controls. The decrease in the head seems to be related to the early response of the brain to X-irradiation. This is the first report that the behavior of free radical such as MCPROXYL in the brain is influenced by X-irradiation. MCPROXYL is thus useful as a novel spin probe for in vivo ESR to monitor the radiation damage in the brain.

The title compound was 11C-labelled in a one-pot procedure using [11C]cyanogen bromide as the key intermediate. Synthesis time was 31–33 min counted from the end of bombardment, affording 1,3-di(2-tolyl)-[11C]guanidine (6) in 87 % decay-corrected radiochemical yield counted from [11C]cyanogen bromide. The specific radioactivity of the product at the end of synthesis was 118 GBq μmol−1 (3.2 Ci μmol−1). Autoradiographic studies on slide-mounted rat brain sections showed specific binding of guanidine (6), but when injected intravenously into Rhesus monkey, brain uptake was very low, indicating that the 1,3-di(2-tolyl)-[11C]guanidine did not cross the blood-brain barrier.

The blood-brain permeabilities of L-[3H]tyrosine and the tyrosine hydroxylase (TH) inhibitor β-[14C]methyl-para-tyrosine ([14C]AMPT) were determined in rat striatum, a brain region rich in TH activity, and in other brain regions containing relatively little TH activity. In striatum, the unidirectional clearance rate (K1) for L-[3H]tyrosine (6.2 ml hg- −1 min−1) was significantly greater than the rates for L-[14C]AMPT (2.8 ml hg−1 min−1) and D-[14C]AMPT (0.8 ml hg−1 min−1). The apparent volume of distribution (Vf) for L-[14C]AMPT in striatum (72.5 ± 4.0 ml hg-1) did not differ from the Vf in other brain regions. The homogeneous distribution of L-[14C]AMPT in rat brain indicates that labeled AMPT is unsuitable for the study of TH in vivo by quantitative autoradiography. © 1994 Wiley-Liss, Inc.

HMPAO-d2 and Deuterium labelled esters of Cytectrenecarbonic ester with alcohols of cyclic amines were synthesized and additional labelled with Tc-99m. The organ distribution in rats showed a higher brain uptake of the cytectrene ester than HMPAO with a far higher Tc-99m concentration ratio brain/blood. The deuterated compounds showed a lower Tc-99m concentration in blood, but no higher uptake in brain.

Esters of ferrocene carbonic acid with aminoalcoholes in the presence of carbonyl donators can exchange their central atom Fe against 99mTc from pertechnetate yielding cytectren-derivatives. Organ distribution of the 99mTc labelled esters showed a high brain uptake.

The complex 99mTcN-CBDTC(CBDTC: N-cyclobutyl dithiocarbamato) was synthesized by the reduction of 99mTcO4− into [99mTcN]2+ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of sodium N-cyclobutyl dithiocarbamate trihydrate. Biodistribution in mice showed that the complex was significantly retained into the brain. The brain uptake(ID%/g) was 3.61, 3.15 and 2.62 and the brain/blood ratio was 1.00, 1.44 and 1.30 at 5, 30 and 60min post-injection, respectively. The results for the complex suggested that it could be a potential brain-perfusion imaging agent.

The goal of this study was the synthesis and in vivo evaluation of a non-peptide compound for studying the NK1 receptor by PET. An N-methyl analogue of CP-122, 721, i. e. CP-643, 051 was chosen. Radiolabelling was achieved by N-methylation of CP-122, 721 with [11C]methyl iodide. Within 38 min (from EOB) 680 MBq of [11C]CP-643, 051 (radiochemical yield: 7%, purity >95%, S.A.: 37 GBq/μmol) was produced. Brain uptake and distribution were studied in anaesthetised pig. In conclusion, due to low brain uptake the compound is not a suitable ligand for studying the NK1 receptor in vivo.

Following subcutaneous injection of the tripeptide H-Pro-[3H]Leu-Gly-NH2 ([3H]PLG) in rats, the profile of intact peptide and its radioactively labeled metabolites was examined both in plasma and in brain tissue. [3H]PLG and metabolites were determined in trichloroacetic acid extracts by reverse-phase paired-ion HPLC. Maximal plasma levels of unmetabolized PLG were reached 6-8 min after administration, after which they decreased with an elimination half-life of 20 min. The uptake of [3H]PLG in the brain ranged from 0.0013% to 0.0017% of the administered dose per g tissue at 6-30 min following subcutaneous injection. After comparing these results with our previous findings with intravenous injection of [3H]PLG, it seemed likely that the subcutaneous route of administration might be more effective in eliciting CNS effects of PLG than the intravenous route of administration. The metabolite profiles in plasma and brain point to an initial cleavage of PLG at the NH2-terminal side and a very rapid degradation of the peptide intermediate H-Leu-Gly-NH2.

This study describes the behaviour of a dual labelled drug, adiphenine, in the rat brain. Macroautoradiographies show images of the brain at different times after injection. Some of the tissue metabolites are identified at the brain level and the passage of the blood brain barrier is compared with tritiated water. The obtained data give very interesting indications on the blood brain distribution and on the metabolism at the brain level. Different techniques of high pressure liquid chromatography, macro- and histoautoradiographies allowed us to visualize how the drug is fixed on cerebral structures, giving indications on its mechanism of action. This fat soluble compound freely crosses the normal blood brain barrier and if labelled with the appropriate emittor could be very useful in nuclear medicine to obtain imaging of the brain.

The uptake index method was used for studies on the passage of various monosaccharides across the blood-retinal and the blood-brain barriers in albino rats. The results indicate large similarities for the hexose transport through the two barriers. Thus a stereo-specific, saturable transport of glucose was observed for both barriers. The carriers involved showed measurable affinity for 2-deoxy-D-glucose, 3-0-methyl-D-glucose, D-mannose and D-galactose, but not for L-glucose, D-fructose or D-ribose. The relative affinities of the various hexoses to the carriers were similar. Phloretin and phloridzin both reduced retinal and brain uptake of D-glucose.

Nicotine is among the compounds that enter the brain very rapidly (blood-flow-limited). It also leaves the brain rapidly; by five minutes, 90% exits, an exit somewhat slower than that of water. In spite of rapid exit, brain levels remain higher than levels in blood over a wide range of blood concentrations. Nicotine enters the fetal circulation from the maternal blood; it enters fetal brain but to a smaller extent than adult brain. Nicotine entry is different from that of amino acid: No interaction of amino acid transport and nicotine could be detected. Most close analogs have no effect on nicotine uptake, but at higher concentrations nicotine uptake is saturable. Nicotine and morphine mutually inhibit each other's uptake. The results suggest an uptake compartment (lipid space) for nicotine shared by morphine.

After intracarotid injection of [3H]beta-casomorphin-5 (beta CM5) in rats, the accumulation of radioactivity was determined in 18 brain regions and the anterior pituitary. The relative accumulation in all regions significantly exceeded that of [3H]inulin by a factor of 2.5, indicating a low but measurable brain uptake of the peptide. In blood-brain barrier-free areas, the accumulation of radioactivity was 15-fold higher than in blood-brain barrier-protected areas. The relative accumulation was not dependent on the total beta CM5 concentration in the range of 0.3-1.1 microM, and was not depressed by 400 microM L-tyrosine. We conclude that beta CM5, like other peptides, is accumulated in the blood-brain barrier-free areas to a relatively high but differing degree, whereas in the areas with a tight endothelium the accumulation is relatively low and nearly uniform. A binding to endothelial cells may contribute to the low accumulation of beta CM5, especially in blood-brain barrier-protected areas.

N(isopropyl)- and N(isobutyl)-Iodo-amphetamine were double labelled with 131I and deuterium. The deuterium labelled radiopharmaceuticals showed in mice and rats a higher brain uptake and a lower blood concentration than the controls (injection of the 131I-labelled amphetamine without deuterium). The deuterium effect ist not increasing with higher deuterium content in the radiopharmaceuticals.

The Oldendorf "brain uptake index" method for estimating and characterizing the transport of circulating substances across the blood-brain barrier in the rat has been widely applied. The present study illustrates that minimizing the volume injected into the circulation to 10 microliters or less is necessary. Otherwise the flow artefacts, induced by the injected volume and the rate of injection, will influence the index. This principle is also relevant to techniques using intracarotid injections for the direct study of cerebral blood flow. The study also elucidates the need for reducing the circulation time after injection to about 5 sec, to avoid artefacts due to metabolism and back diffusion to the circulation of the substances studied.

Local cerebral glucose utilization was measured by the [14C]2-deoxy-d-glucose method in conscious control and hyperketonemic rats. Hyperketonemia was induced by 3 days of starvation or by infusion of 3- hydroxybutyrate in fed rats. These treatments produced combined blood ketone body concentrations (acetoacetate + 3-hydroxybutyrate) of from 1.2 to 2.4 mM. Neither treatment significantly affected glucose utilization in any of the 15 brain regions studied. These observations indicate that hyperketonemia in resting, conscious rats does not interfere with brain uptake and phosphorylation of glucose.

— The uptake into brain and the incorporation into brain protein of intraperitoncally administered, labelled amino acids has been studied in myelinating rats during prolonged hyperphenylalaninaemia maintained by administration of p-chlorophenylalanine. Compared with controls, there was a 50% reduction in both uptake and incorporation into protein of leucine and a parallel reduction in the acid-soluble leucine pool. With glycine and lysine no such changes were observed. On the other hand, when each of the three amino acids was injected directly into the brain, the only significant differences observed between controls and hyperphenylalaninaemic animals were again with leucine, which showed an increased incorporation into protein and an increased specific activity in the otherwise reduced acid-soluble pool. It is concluded that hyperphenylalaninaemia reduces the rate of transport of leucine into the brain and hence reduces the brain pool of leucine, but that any effects on protein synthesis are small. The validity of the model, and the implications of the findings, in relation to phenylketonuria, are discussed.

In developing new brain perfusion imaging agents for single photon emission computed tomography (SPECT), five 99mTc-labeled neutral bis(aminoethanethiol) (BAT) derivatives capable of crossing the blood-brain barrier are reported. The five ligands are prepared by two versatile synthetic methods that can specifically introduce substituents on one of the carbons between two nitrogens. These ligands formed stable and neutral complexes with the reduced 99mTc, using either Sn(II) or sodium borohydride to reduce sodium [99mTc]pertechnetate. The biodistribution in rats was evaluated with [125I]iodoantipyrine, a freely diffusible tracer, as the internal reference. Compounds with a free hydroxyl group, 6 and 15, showed lower brain uptake. High initial brain uptake was observed for compounds 10 and 14, 1.28 and 2.30% dose/organ, respectively. Compounds of this type may be used as a basis for future structural modification to improve brain uptake and retention.