Immobilization of Amano lipase AK from Pseudomonas fluorescens on different types of chitosan-containing supports: use in the kinetic resolution of rac-indanol.

Amano lipase AK from P. fluorescens was immobilized on different types of chitosan-containing supports. Chitosan lower molecular weight (2.5%), chitosan lower molecular weight/sodium alginate (2.5%/2.5%) and chitosan lower molecular weight/carrageenan (2.5%/2.5%) allowed the highest values of immobilization yields (IY) of 81, 81 and 83%, respectively. Best activity results were achieved using chitosan average molecular weight (5%) and chitosan lower molecular weight/sodium alginate (2.5%/2.5%) as support, with values of 1.40 and 1.30 UpNPB/ggel and with recovery activities of 45.75 and 35.6%, respectively. These derivatives were evaluated in the kinetic resolution of rac-indanol to obtain a key intermediate in the synthesis of a drug used in the treatment of Parkinson's disease. The most efficient derivatives in the kinetic resolution were lipase immobilized on chitosan average molecular weight (5.0%) and chitosan low molecular weight/sodium alginate, the latter leading to obtaining both (S)-indanol and (R)-indanyl acetate with > 99% ee and 50% conversion.

Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study.

Monoamine oxidases (MAOs) catalyze the degradation of a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, whose imbalance is extensively linked with the biochemical pathology of various neurological disorders, and are, accordingly, used as primary pharmacological targets to treat these debilitating cognitive diseases. Still, despite this practical significance, the precise molecular mechanism underlying the irreversible MAO inhibition with clinically used propargylamine inhibitors rasagiline and selegiline is still not unambiguously determined, which hinders the rational design of improved inhibitors devoid of side effects current drugs are experiencing. To address this challenge, we present empirical valence bond QM/MM simulations of the rate-limiting step of the MAO inhibition involving the hydride anion transfer from the inhibitor α-carbon onto the N5 atom of the flavin adenin dinucleotide (FAD) cofactor. The proposed mechanism is strongly supported by the obtained free energy profiles, which confirm a higher reactivity of selegiline over rasagiline, while the calculated difference in the activation Gibbs energies of ΔΔG‡ = 3.1 kcal mol-1 is found to be in very good agreement with that from the measured literature kinact values that predict a 1.7 kcal mol-1 higher selegiline reactivity. Given the similarity with the hydride transfer mechanism during the MAO catalytic activity, these results verify that both rasagiline and selegiline are mechanism-based irreversible inhibitors and offer guidelines in designing new and improved inhibitors, which are all clinically employed in treating a variety of neuropsychiatric and neurodegenerative conditions.

Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors.

Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson's disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC50 = 0.11 µM), L8 (IC50 = 0.18 µM), L16 (IC50 = 0.27 µM) and L17 (IC50 = 0.48 µM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.

Design of selegiline-loaded bio-nanosuspension for the management of depression using novel bio-retardant from Manilkara zapota.

Objective: Depression is one of the most frequent psychiatric and potentially life-threatening disorders. This research work can offer a potential for delivery of selegiline moiety via ocular route in bio-nanosuspension mode for the effective management of depression after preclinical performance screening. Methods: The selegiline-loaded bio-nanosuspension was prepared using novel bio-retardant isolated from fruit pulp of Manilkara zapota (Sapodilla) by sonication solvent evaporation method with different ratios (0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and 1%) and with standard polymer HPMC (0.1%, 0.2%, 0.3%, 0.4%, and 0.5%). The prepared formulations were evaluated for pH stability studies, %entrapment efficiency, in vitro drug release, particle size, polydispersity index (PDI), zeta potential, and stability studies. Results: The prepared bio-nanosuspension was subjected to the best formulation based on comparison of above-mentioned evaluation parameters, so Fb2 (0.1%) formulation was found to be the best formulation showing an R2 value of 0.9814, T50% of 29.7 h, and T80% of 65.25 h. According to the release kinetics, the best fit model was found to be the Korsmeyer-Peppas with the Fickian diffusion (Higuchi matrix) as the mechanism of drug release. Manilkara zapota (Sapodilla) provided excellent stability for the formulation and resulting particle size for the best formulation was found to be 252 nm. The bio-nanosuspension had PDI of 0.35 with zeta potential of -8.91 mV. Conclusion: The prepared bio-nanosuspension was found to be safe and compatible with the ophthalmic delivery for treatment of depression.

Pharmacokinetics and pharmacodynamics of intranasally administered selegiline nanoparticles with improved brain delivery in Parkinson's disease.

Selegiline, a well-known anti-Parkinson agent, is reported to be associated with poor oral bioavailability and safety. Therefore, we formulated selegiline as chitosan nanoparticles and evaluated its pharmacokinetics and pharmacodynamics after intranasal administration to rats relative to those after oral administration. The optimized formulation exhibited spherical nanoparticles with more than 90% drug loading and steady in vitro and ex vivo drug release. Selegiline concentrations in the brain and plasma were 20- and 12-fold higher, respectively, after intranasal administration than after oral administration. Treatment with intranasal nanoparticles was also associated with better performance in locomotor activity, catalepsy, and stride length tests and significantly increased dopamine, catalase activity, and glutathione content in the brain. Therefore, intranasally administered selegiline nanoparticles holds superior therapeutic value compared to oral administration and can be a promising approach for the treatment of Parkinson's disease.

Potent and selective MAO-B inhibitory activity: amino- versus nitro-3-arylcoumarin derivatives.

In this study we synthesized and evaluated a new series of amino and nitro 3-arylcoumarins as hMAO-A and hMAO-B inhibitors. Compounds 2, 3, 5 and 6 presented a better activity and selectivity profile against the hMAO-B isoform (IC50 values between 2 and 6nM) than selegiline. In general, the amino derivatives (4-6) proved to be more selective against MAO-B than the nitro derivatives (1-3). Additionally, a theoretical study of some physicochemical properties, PAMPA and reversibility assays for the most potent derivative, and molecular docking simulations were carried out to further explain the pharmacological results, and to identify the hypothetical binding mode for the compounds inside the hMAO-B.

In vivo evaluation in cynomolgus monkey brain and metabolism of [¹8F]fluorodeprenyl: a new MAO-B pet radioligand.

In this study, we evaluated the in vivo characteristics of a new monoamine oxidase type B (MAO-B) radioligand, [¹8F]fluorodeprenyl, by positron emission tomography (PET) in two cynomolgus monkeys. The brain uptake of [¹8F]fluorodeprenyl was more than 7% (600% SUV) of the total injected radioactivity and similar to that of [¹¹C]deprenyl, an established MAO-B radioligand. The highest uptake was observed in the striatum, one of the MAO-B-rich regions, with a peak at approximately 2-3 min after injection, followed by lower uptake in the thalamus and the cortex and lowest uptake in the cerebellum. Brain uptake of [¹8F]fluorodeprenyl was largely inhibited by preadministration of the MAO-B inhibitor, L-deprenyl, whereas clorgyline, a MAO Type A blocker, had no significant inhibitory effect, thus demonstrating selectivity for MAO-B. [¹8F]Fluorodeprenyl showed relatively slow metabolism with the presence of two radiometabolite peaks with similar retention time as the labeled metabolites of [¹¹C]deprenyl. These results suggest that [¹8F]fluorodeprenyl is a potential PET radioligand for visualization of MAO-B activity.

Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents.

Monoamine oxidase (MAO) enzymes catalyze the oxidative deamination of amines and neurotransmitters and inhibitors of MAO are useful as neuroprotectants. This work evaluates the human MAO-catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin, to the directly-acting neurotoxic metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) measured by High-Performance Liquid Chromatography (HPLC), and this approach is subsequently used as a new method for screening of MAO inhibitors and protective agents. Oxidation of MPTP by human MAO-B was more efficient than by MAO-A. R-Deprenyl, a known neuroprotectant, norharman (ß-carboline), 5-nitroindazole and menadione (vitamin K3) inhibited MAO-B and reduced the formation of toxic pyridinium cations. Clorgyline and the ß-carbolines, harman and norharman, inhibited the oxidation of MPTP by MAO-A. Cigarette smoke, as well as the naturally occurring ß-carbolines (norharman and harman) isolated from smoke and coffee inhibited the oxidation of MPTP by MAO-B and/or MAO-A, suggesting protective effects against MPTP. The results show the suitability of the approach used to search for new MAO inhibitors with eventual neuroprotective activity.

Ring opening of pymisyl-protected aziridines with organocuprates.

The pyrimidine-2-sulfonyl (pymisyl) group is introduced as a new protecting group that can be used to activate aziridines towards ring opening. It is readily introduced and removed under mild conditions. Regioselective ring opening of pymisyl-protected 2-methyl-aziridine with organocuprates gives the corresponding sulfonamides in high yields, and the pymisyl group can subsequently be removed upon treatment with a thiolate. The versatility of this new nitrogen protecting group is illustrated with a new synthesis of Selegiline, a monoamine oxidase-B inhibitor marketed for the treatment of Parkinson's disease.

Supplementation of deprenyl attenuates age associated alterations in rat cerebellum.

Aging, a multifactorial process of enormous complexity is characterised by physio-chemical and biological aspects of cellular functions. It is closely associated with changes in metabolism of various biological molecules in the system. In the present study, we have investigated the effect of deprenyl on cerebellum during ageing process in male Wistar rats with respect to the changes in levels of protein, glycoproteins and amino acids in experimental rats of three age groups (6, 12 and 18 months old). Intraperitoneal administration of liquid deprenyl (2 mg/kg body weight/day for a period of 15 days i.p., significantly P < 0.05) attenuated age-associated alterations in the levels of amino acids (taurine, aspartate, glutamate, arginine, hydroxy proline and homocysteine), protein content and glycoprotein components (hexose and hexosamine) in the rat cerebellum. The results of the present investigation indicate that the protective effect of deprenyl is probably related to its ability to strengthen the neuronal membrane by its membrane stabilizing action or to a counteraction of free radicals by its antioxidant property.

Development and Characterization of Nasal Delivery of Selegiline Hydrochloride Loaded Nanolipid Carriers for the Management of Parkinson's Disease.

INTRODUCTION: Parkinson's Disease (PD) is one of the most common age-related neurodegenerative disorders which is marked with the loss of dopaminergic neurons. The present study performed on the nose to brain delivery of selegiline hydrochloride loaded nano lipid carrier, suggests that the nasal route is a good mean of targeting the drug directly into the brain. METHODS AND MATERIALS: Nanostructured lipid carriers were prepared by using hot homogenization. Selegiline hydrochloride loaded NLCs and rotenone treatment were given at a dose of 10 mg/kg administered from 14th day to 28th day. Behavioral parameters were determined at 7th, 14th, 21st and 28th day. On the 28th day, animals were sacrificed for biochemical estimation. RESULTS: The optimized drug loaded NLC formulation has shown 93±5.25% entrapment efficiency and 51.96% loading capacity. Optimized NLCs formulation has shown 70% release within 10 hours and after that, the release of the drug is sustained up to 22 hours (97%). Pharmacological action of the drug was found to restore the behavioral parameters in rotenone-induced rats. CONCLUSION: Nano Lipid Carrier (NLCs) therapeutics has emerged as a prominent method for the treatment of Parkinson's Disease (PD) as it offers targeted delivery and enhances the therapeutic efficacy of neurotherapeutics. It is concluded from the studies that, Selegiline HCl loaded nano lipid carrier which was administered through nasal route has the potential to be used in the management therapy of Parkinson's disease.

Biopharmaceutical Potential of Selegiline Loaded Chitosan Nanoparticles in the Management of Parkinson's Disease.

BACKGROUND: Selegiline hydrochloride, a hydrophilic anti-Parkinson' moiety, undergoes extensive first-pass metabolism and has low bioavailability. A process to obtain of selegiline (SH) loaded chitosan nanoparticles was attempted to circumvent the above problem, through intranasal delivery. METHODS: SH loaded polymeric nanoparticles were prepared by ionic gelation of chitosan with tripolyphosphate, and stabilized by tween 80/ poloxamer 188. The resulting nanoparticles (NPs) were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, entrapment efficiency, particle size, zeta potential and surface morphology by scanning electron microscopy. Further, they were schematically evaluated for mucoadhesive strength, in-vitro drug release, release kinetics, pharmacokinetics, catalepsy, akinesia, in-vivo lipid peroxidation, nitrite levels, glutathione, catalase enzyme levels in brain and physicochemical stability parameters. RESULTS: Selegiline nanoparticles (SP18) produced were in size of 63.1 nm, polydispersity index of 0.201, zeta potential of +35.2 mV, mucoadhesion of 65.4% and entrapment efficiency of 74.77%. Selegiline showed biphasic release from nanoparticles, over a period of 36 h, with Fickian diffusion controlled release profile. Maximum concentration of SH in plasma was recognized as 52.71 ng/ml at 2 h for SP18, 20.09 ng/ml at 1 h for marketed formulation, and 21.69 ng/ ml for drug solution. SH loaded NPs showed a reversive effect in catalepsy and akinesia behaviour. This effect was especially pronounced in rats receiving SH loaded CS-NPs. Significant decrease in lipid peroxidation and nitrite concentration; increase in reduced glutathione and catalase enzyme levels were obtained due to antioxidant characteristics of SH, which turned to be useful to treat Parkinson's disease. CONCLUSION: Selegiline loaded chitosan nanoparticles form an effective non-invasive drug delivery system of direct nose to brain targeting in Parkinson's disease.

Optimization and validation of a dissolution test for selegiline hydrochloride tablets by a novel rapid HPLC assay using a monolithic stationary phase.

The present study reports the optimization and validation of a dissolution test for selegiline.HCl tablets using a new high-performance liquid chromatographic (HPLC) method. Rapid separation of the analyte from sample matrix was achieved in less than 60s using a Cromolith RP-18e monolithic column using UV detection at 220 nm. Thorough validation of the assay based on pre-defined criteria included linearity, LOD/LOQ, accuracy, precision, selectivity and ruggedness. The dissolution test was optimized in terms of dissolution medium, basket (type I)/paddle (type II) agitation and rotation speed. Its ruggedness was also validated. The presented analytical and dissolution procedures are currently being applied in the quality and stability control of Cosmopril tablets (5mg/tablet selegiline.HCl, Cosmopharm Ltd., Korinthos, Greece).

Selegiline Nanoformulation in Attenuation of Oxidative Stress and Upregulation of Dopamine in the Brain for the Treatment of Parkinson's Disease.

Objective of this study was to determine whether the prepared nanoemulsion would be able to deliver selegiline to the brain by intranasal route, improving its bioavailability. Antioxidant activity, pharmacokinetic parameters, and dopamine concentration were determined. Oxidative stress models, which had Parkinson's disease-like symptoms, were used to evaluate the antioxidant activity of nanoemulsion loaded with selegiline in vivo. The antioxidant activity was evaluated by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay and reducing power assay, which showed high scavenging efficiency for selegiline nanoemulsion compared to pure selegiline. Biochemical estimation results showed that the levels of antioxidant enzymes, including glutathione and superoxide dismutase, were increased, whereas the levels of thiobarbituric acid-reactive substances were decreased in intranasally administered selegiline nanoemulsion-treated group when compared with haloperidol-induced Parkinson's disease group (control). Moreover, selegiline nanoemulsion was found to be successful in decreasing the dopamine loss, indicating that nanoemulsion is a potential approach for intranasal delivery of selegiline to decrease the damage due to free radicals, thus avoiding consequent biochemical alterations that arise during Parkinson's disease. Brain:blood ratio of 2.207 > 0.093 of selegiline-loaded nanoemulsion (intranasally administered) > selegiline solution (administered intravenously), respectively, at 0.5 hours showed direct nose-to-brain delivery of drug bypassing blood-brain barrier. Selegiline-loaded nanoemulsion administered intranasally showed significantly high dopamine concentration (16.61 ± 3.06 ng/mL) compared to haloperidol-treated rats (8.59 ± 1.00 ng/mL) (p < 0.05). In this way, intranasal delivery of selegiline nanoemulsion might play an important role in the better management of Parkinson's disease.

Differential effects of selegiline on glucose synthesis in rabbit kidney-cortex tubules and hepatocytes. In vitro and in vivo studies.

The action of selegiline, a selective and irreversible inhibitor of monoamine oxidase B, commonly applied in the therapy of Parkinson's disease, on glucose formation was investigated in isolated rabbit hepatocytes and kidney-cortex tubules, maintaining the whole body glucose homeostasis via gluconeogenic pathway activity. An intensive hepatic metabolism of selegiline resulted in formation of selegiline-N-oxide, desmethylselegiline, methamphetamine and amphetamine, whereas during slow degradation of the drug in freshly isolated renal tubules selegiline-N-oxide was mainly produced. At 100 microM concentration selegiline markedly diminished glucose synthesis in isolated renal tubules incubated with dihydroxyacetone or alanine+glycerol+octanoate (by about 60 and 30%, respectively), while at 5 microM concentration a similar degree of inhibition was achieved in renal tubules grown in primary culture under the same conditions (about 40 and 60%, respectively). Moreover, desmethylselegiline and selegiline-N-oxide considerably diminished glucose production in renal tubules whereas selegiline and its metabolites did not affect gluconeogenesis in hepatocytes. Contrary to control animals, following selegiline administration to alloxan-diabetic rabbits for 8 days (10 mg kg(-1) body wt. daily) the blood glucose and serum creatinine levels were significantly diminished, suggesting a decrease in renal gluconeogenesis and improvement of kidney functions. Since in renal tubules selegiline induced a decline in the intracellular levels of gluconeogenic intermediates and ATP content accompanied by a decrease in oxygen consumption in both kidney-cortex and hepatic mitochondria it seems possible that its inhibitory action on renal gluconeogenesis might result from an impairment of mitochondrial function, while an intensive selegiline metabolism in hepatocytes causes decrease of its concentration and in consequence no inhibition of gluconeogenesis. In view of these observations it is likely that an increased risk of selegiline-induced hypoglycemia might be expected particularly in patients exhibiting an impairment of liver function and following transdermal administration of this drug, i.e. under conditions of increased serum selegiline concentrations.

Cortical laminar tau deposits and activated astrocytes in Alzheimer's disease visualised by 3H-THK5117 and 3H-deprenyl autoradiography.

Hyperphosphorylated tau protein deposits and, inflammatory processes are characteristic components of Alzheimer disease (AD) pathology. We here aimed to visualize in vitro the distribution of tau deposits and activated astrocytes across the cortical layers in autopsy AD brain tissue using the radiotracers 3H-THK5117 and 3H-deprenyl. 3H-THK5117 and 3H-deprenyl autoradiographies were carried out on frozen brain sections from three AD patients and one healthy control. 3H-THK5117 showed a distinct laminar cortical binding similar to 3H-deprenyl autoradiography, with an extensive binding in the superficial and deep layers of the temporal neocortices, whereas the middle frontal gyrus showed an even binding throughout the layers. Globally, eventhough some differences could be observed, AT8 (tau) and GFAP (astrocyte) immunostaining showed a laminar pattern comparable to their corresponding radiotracers within each AD case. Some variability was observed between the AD cases reflecting differences in disease phenotype. The similar laminar cortical brain distribution of tau deposits and activated astrocytes supports the hypothesis of a close pathological interconnection. The difference in regional binding patterns of 3H-THK5117 and AT8 antibody staining suggest additional tau binding sites detectable by 3H-THK5117.

A comparison of drug-seeking behavior maintained by D-amphetamine, L-deprenyl (selegiline), and D-deprenyl under a second-order schedule in squirrel monkeys.

L-Deprenyl (selegiline) is used in the treatment of Parkinson's disease and has been proposed as an aid for cigarette smoking cessation and a treatment for psychostimulant abuse. L-Deprenyl is metabolized in the body to L-methamphetamine and L-amphetamine, suggesting that it may have abuse potential. The current study assessed whether L-deprenyl or its isomer would maintain drug-seeking behavior on a second-order schedule and whether L-deprenyl would alter drug-seeking behavior maintained by D-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash, and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of D-amphetamine (0.56 mg/kg), administered over a 2-min period at the end of the session. When responding was stable, saline or different i.v. doses of D-amphetamine (0.3-1.0 mg/kg), L-deprenyl (0.1-10.0 mg/kg), and D-deprenyl (0.1-3.0 mg/kg) were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg L-deprenyl intramuscularly 30 min prior to D-amphetamine baseline sessions. D-Amphetamine maintained high rates of drug-seeking behavior on the second-order schedule. D-Deprenyl maintained high rates of drug-seeking behavior similar to D-amphetamine. L-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with L-deprenyl failed to alter drug-seeking behavior maintained by D-amphetamine. These results indicate that D-deprenyl, but not L-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behaviors are actively maintained by D-amphetamine, L-deprenyl, at doses that specifically inhibit type B monoamine oxidase, may not be effective as a treatment.

The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30.

The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective-neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Abeta peptide, since APP is a metaloprotein, with an iron responsive element 5d'UTR similar to transferring and ferritin.

Deprenyl: from chemical synthesis to neuroprotection.

During the last decades (-)-deprenyl has become the golden standard of MAO-B inhibitors. It possesses dopamine potentiating and antioxidant properties; however, its effects cannot be explained solely by the enzyme inhibitory action. (-)-Deprenyl prevents the toxicity of certain selective neurotoxins and recently it was demonstrated to increase cell-cell adhesion as well. The complexity of its pharmacological effects reflects the action of both the parent compound and the active metabolites. (-)-Deprenyl and related propargylamines (DRPs) show neuroprotective features in a variety of in vitro and in vivo models that is dependent on the propargyl moiety. The main presumptive targets to date include glyceraldehyde-3-phosphate dehydrogenase, poly(ADP-ribose) polymerase, some kinase cascades, as well as pro- and antiapoptotic proteins, beside the inhibition of MAO-B. The antiapoptotic activity of DRPs converges upon the maintenance of mitochondrial integrity, due to the initiation of a complex transcriptional program, the details of which are yet to be elucidated.

Automated radiosynthesis of [(11)C]L-deprenyl-D2 and [(11)C]D-deprenyl using a commercial platform.

Two (11)C-labelled PET tracers, (R)-N-[(11)C]methyl-N-(3,3-dideuteropropargyl)-1-phenylpropan-2-amine ([(11)C]L-deprenyl-D2, [(11)C]DED) and (S)-N-[(11)C]methyl-N-propargyl-1-phenylpropan-2-amine ([(11)C]D-deprenyl, [(11)C]DDE) were synthesised. One step N-alkylation with [(11)C]MeI or [(11)C]MeOTf was performed using the automated platform TRACERlab® FX-C Pro. The labelled products were obtained with (37±15)% (n=10) (end of synthesis, decay corrected from [(11)C]MeI) radiochemical yields from [(11)C]MeI after 38±3min synthesis time. In all cases, radiochemical purity was over 99% when [(11)C]MeOTf was used. This synthesis using a commercial platform makes these tracers more accessible for clinical research purposes.