[show abstract][hide abstract] ABSTRACT: In order to study the effects of crystal structures on resolvabil-ity, a CSD (Cambridge Crystallographic Database) study has been carried out on 1-phenylethylammonium diastereomeric salt pairs with available crystal structures. The structures of the diastereomers of the salts are analyzed, compared and grouped. The structural features are set against the resolution results. The effects of three types of structural features on the resolution effi-ciency are demonstrated.
[show abstract][hide abstract] ABSTRACT: Optical resolution methods were established for racemic 1-(1-naphthyl) ethylamine. The resolving agents were synthesized by N-derivatizing (R)-1-(1-naphthyl) ethylamine with dicarboxylic acids. Oxalic, malonic, and succinic acid derivatives were found to be suitable resolving agents. These resolutions are parallel to a series of optical resolutions of 1-phenylethylamine which had been previously performed by our research group using similar derivative resolving agents (Balint et al., Tetrahedron: Asymmetry 2001;12:1511-1518.) The comparison of the results of the enantiomer separations is performed. The diastereomeric salts formed with (R)-N-[1-(1-naphthyl)ethyl]oxalamic acid were investigated by single crystal X-ray diffraction. The crystal structures were compared with the previously published structures of the diastereomers of the phenyl-substituted analogue, namely (R)- and (S)-1-phenylethylammonium (R)-N-(1-phenylethyl)oxalamates (Balint et al., Tetrahedron: Asymmetry 2001;12:1511-1518).
[show abstract][hide abstract] ABSTRACT: Racemic 1-phenylethylamine was optically resolved by its own derivative formed with glutaric acid namely (+)-(R)-N-(1-phenylethyl)glutaramic acid. The amide acid resolving agent was synthesized from (+)-(R)-1-phenylethylamine by N-derivatization. The glutaric acid derivative was the next in a homologous series of dicarboxilic acid derivatized resolving agents of racemic 1-phenylethylamine. Resolution results obtained with the oxalic, malonic, and succinic acid derivatives were previously discussed(1). Each of the above derivative resolving agents could be successfully applied as resolving agents of 1-phenylethylamine. The efficiency of the present optical resolution using (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent was remarkably inferior to the results obtained by its shorter chained homologues(1). Use of achiral additives, like urea, thiourea, N-methylurea, and N,N'-dimethylurea caused large increase in the efficiency of the resolution by (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent. Precipitated salts obtained in the resolutions performed in the presence of the additives were investigated by thermoanalysis, X-ray powder diffraction, and optical microscopy. Based on the analytical data, the improvement of the resolution results was attributed to the influence of the additives on the crystal nucleation processes of the diasteromeric salts.
[show abstract][hide abstract] ABSTRACT: Optical resolution of racemic-phenylalanine through its N-formyl derivative with a 1-phenylethylamine resolving agent is an effective procedure. Differential scanning calorimetry, single crystal X-ray diffraction and optical microscopy were used in the investigation of the resolution process. It was found that the thermodynamic properties of the given system would not allow the efficient enantiomer separation. Kinetic effects during the crystal formation have been discovered by the comparison of the crystal morphologies of the two diastereomers. The crystal structure of the less soluble diastereomer (S)-(−)-1-phenylethylammonium (S)-(+)-N-formylphenylalaninate salt has been determined and discussed.
[show abstract][hide abstract] ABSTRACT: The efficiency of the resolution of N-formylphenylalanine was remarkably improved using (S)-(+)-2-benzylaminobutanol resolving agent in acetone. The efficiency of the resolution strongly depended on the quality of the solvent. Nevertheless, solvate formation did not occur during the process. The nature of the solvent-dependence was studied. The solid-melt binary phase diagram of the diastereomeric salts formed during the resolution by (S)-(+)-2-benzylaminobutanol was measured and discussed. It was recognized that the (S)-(+)-benzylaminobutanol (S)-(+)-N-formylphenylalanine salt exists in two polymorphic modifications.The effect of structurally related chiral and achiral auxiliary reagents in the above resolution was also studied. Thus, (S)-(+)-2-benzylaminobutanol was applied together with an (R)-(+)-1-phenylethylamine auxiliary resolving agent and benzylamine was used as a half-equivalent achiral basic reagent in a Pope–Peachey type resolution of N-formylphenylalanine by (S)-(+)-2-benzylaminobutanol. The results are compared to those obtained by the structurally related (R)-(+)-1-phenylethylamine chiral auxiliary.
[show abstract][hide abstract] ABSTRACT: Previously, we used positron emission tomography (PET) for studying the pharmacokinetics of rac-[11C]mirtazapine in living brain. Our findings showed that rac-[11C]mirtazapine has suitable properties for PET neuroimaging. However, separate studies of enantiomers are typically required for characterizing the pharmacokinetics of a racemic drug. Therefore, we have determined the whole-body distribution and brain pharmacokinetics of S- and R-[11C]mirtazapine in pigs. The enantiomers of [11C]mirtazapine produced similar effective doses of radioactivity in most body organs, except for the brain, in which the dose was approximately 40% higher after injection of S-[11C]mirtazapine than the antipode. Kinetic analyses of dynamic brain PET recordings showed that values for regional accumulation of compound (k3) were significantly higher for S-[11C]mirtazapine than for the antipode, while the values for clearance of compounds from tissue to circulation (k2) were consistently lower for S-[11C]mirtazapine than for the R-form. No reliable difference occurred in the rate of metabolism of S- and R-[11C]mirtazapine in the bloodstream of the pigs. The present findings indicate that enantioselective processes affect the cerebral pharmacokinetics of rac-mirtazapine.
European Neuropsychopharmacology 08/2006; 16(5):350-7. · 4.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have developed [(11)C]mirtazapine as a ligand for PET studies of antidepressant binding in living brain. However, previous studies have determined neither optimal methods for quantification of [(11)C]mirtazapine binding nor the pharmacological identity of this binding. To obtain that information, we have now mapped the distribution volume (V(d)) of [(11)C]mirtazapine relative to the arterial input in the brain of three pigs, in a baseline condition and after pretreatment with excess cold mirtazapine (3 mg/kg). Baseline V(d) ranged from 6 ml/ml in cerebellum to 18 ml/ml in frontal cortex, with some evidence for a small self-displaceable binding component in the cerebellum. Regional binding potentials (pBs) obtained by a constrained two-compartment model, using the V(d) observation in cerebellum, were consistently higher than pBs obtained by other arterial input or reference tissue methods. We found that adequate quantification of pB was obtained using the simplified reference tissue method. Concomitant PET studies with [(15)O]-water indicated that mirtazapine challenge increased CBF uniformly in cerebellum and other brain regions, supporting the use of this reference tissue for calculation of [(11)C]mirtazapine pB. Displacement by mirtazapine was complete in the cerebral cortex, but only 50% in diencephalon, suggesting the presence of multiple binding sites of differing affinities in that tissue. Competition studies with yohimbine and RX 821002 showed decreases in [(11)C]mirtazapine pB throughout the forebrain; use of the multireceptor version of the Michaelis-Menten equation indicated that 42% of [(11)C]mirtazapine binding in cortical regions is displaceable by yohimbine. Thus, PET studies confirm that [(11)C]mirtazapine affects alpha(2)-adrenoceptor binding sites in living brain.
[show abstract][hide abstract] ABSTRACT: The method of drying resorcinol–formaldehyde (RF) gels influences the structure and gas adsorption capacity of the resulting networks as well as of their carbonized derivatives. Small angle X-ray scattering (SAXS) reveals the presence of submicroscopic clusters both in the RF gels and in the carbon gels, whose size, of the order of tens of nanometres, is consistent with SEM observations. Xerogels, obtained by heating the RF hydrogel in an inert atmosphere, have the most compact structure and display the lowest specific surface area (<900 m2/g). The highest surface area is found in the gel lyophilized after freeze-drying in t-butanol (>2500 m2/g), but the resulting carbon cryogel is not structurally stable, the measured surface area decreasing with time. Supercritical extraction with liquid carbon dioxide yields aerogels with an intermediate value for the surface area (ca. 1000 m2/g). Carbonization causes a reduction in the size of the elementary spheres (from 27 to 8 nm) in the case of the aerogels, while an increase (from 10 to 22 nm) is observed for the xerogels. The adsorption sites in the carbon gels are located principally in irregular spaces between monomer units. For the carbonized cryogels the specific surface area derived from SAXS is greater than that found by low temperature gas adsorption. This phenomenon is interpreted in terms of restricted pore size, which limits the access of gas molecules. By contrast, in the RF gels the SAXS-derived surface areas are substantially smaller than those measured by gas adsorption.
Microporous and Mesoporous Materials 07/2005; 86:124-133. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Many actions of antidepressant drugs cannot yet be studied using positron emission tomography (PET) neuroimaging due to lack of suitable radioligands. We believe that mirtazapine, radiolabeled with C-11, might be suitable for PET neuroimaging of alpha2-adrenoceptors in selected regions of the living human brain.
To determine the regional central biodistribution and pharmacokinetics of [N-methyl-11C]mirtazapine in humans.
Five healthy volunteers received an intravenous injection of [N-methyl-11C]mirtazapine for evaluating its metabolism, biodistribution and pharmacokinetics.
[N-methyl-11C]Mirtazapine entered the brain readily, with initial clearance from blood to tissue (K1) ranging from 0.31 ml/ml/min in amygdala to 0.54 ml/ml/min in thalamus. The rate of metabolism of [N-methyl-11C]mirtazapine in the bloodstream was relatively slow, with 20-40% of [11C]-derived radioactivity still present as parent compound at 60 min post-injection. The clearance of [N-methyl-11C]mirtazapine from the tissue compartment (k2') ranged from a low of 0.03 min(-1) in amygdala to a high of 0.06-0.07 min(-1) in thalamus and cerebellum. The volume of distribution (Ve') of [N-methyl-11C]mirtazapine was markedly greater in hippocampus and amygdala (11.3-12.0) than in cerebellum (6.7), with intermediate levels in the thalamus (9.4).
[N-methyl-11C]Mirtazapine has suitable properties for PET neuroimaging. We envision [N-methyl-11C]mirtazapine as a molecular probe for PET imaging of antidepressant actions at sites such as alpha2-adrenoceptors in the living human brain.
[show abstract][hide abstract] ABSTRACT: Activated carbon prepared from poly(ethylene terephthalate) was treated with nitric acid at ambient temperature and at the
boiling point of the suspension. The morphology of the products was investigated by scanning electron microscopy, nitrogen
adsorption observations and by small-angle X-ray scattering. The effect of acidic treatment on acid–base surface properties
was studied by quasi-equilibrium potentiometric acid–base titration. It is found that the morphology of the products obtained
after low-temperature treatment is similar, but high-temperature acid treatment induces a major reduction both in the surface
area and in the fine pore structure. The intrinsic microporous character of the original carbon, however, is conserved. Both
for the morphology and for the surface chemistry, the temperature of the treatment is more important than its duration. Nevertheless,
while the morphology is affected significantly only at high temperature, the acid–base properties are modified in all the
KeywordsActivated carbon–Chemical treatment–Adsorption–Scanning electron microscopy–Small-angle X-ray scattering–Quasi-equilibrium acid-base titration
[show abstract][hide abstract] ABSTRACT: Complementary techniques, including low-temperature nitrogen adsorption and small-angle X-ray scattering (SAXS), are applied to detect the effects of surface functionalization on the morphology of activated carbon derived from poly(ethylene terephthalate) (PET). Scanning electron microscopy (SEM) is also employed as an auxiliary method to visualize the surface below the micron scale. The SEM images reveal a micron-sized ridgelike texture. Room temperature acid treatment makes the ridges become more pronounced, while treatment with boiling acid uncovers fiberlike structures of roughly 1 microm diameter. All samples display an apparent surface fractal dimension of Ds = 2.4 in the wave vector range 0.001-0.02 A(-1). Nitric acid at room temperature increases the surface oxygen content only by 3 at. %, while all the adsorption properties and structural parameters reported in this paper are virtually unaffected. Significant differences in the morphology at submicron scales appear only after boiling acid treatment. The resulting carbon remains highly microporous, but the loss of Brunauer-Emmett-Teller (BET) surface area from about 1150 to 304 m2/g is approximately 75%. In addition to the principal peak at around 8 A, fresh peaks appear in the polydisperse Horvath-Kawazoe (HK) pore size distribution owing to the burnoff of intervening walls. The average width of the slitlike pores calculated from the Dubinin-Radushkevich (DR) plot increases from 8.4 to 11 A. The minimum slit width where the applied probe molecules, that is, nitrogen and hexane, can enter increases from about 5 to about 5.4 A. The separation distance of the basic structural units is practically unchanged. When, however, this carbon is in contact with hexane, this distance expands from about 19 to 27 A. The swelling is consistent with the deformable nature of this sample also illustrated by the low-pressure hysteresis and the reduced helium density. Particular attention was paid to the surface areas derived from low-temperature nitrogen adsorption and X-ray measurements. Owing to the wide spatial range of the structures in these samples, estimates of the specific surface area of activated carbons can be substantially in error unless both upper and lower q ranges of the SAXS spectra are taken into account. Surface areas derived from the adsorption data either by the BET or the DR approaches were always below the values obtained by standard SAXS. As an example, the carbon sample functionalized at room temperature gave surface area values of 1114, 1293, and 1970 m2/g, respectively. The possibility that this difference is caused by inaccessible pores was excluded by contrast variation measurements with hexane.
[show abstract][hide abstract] ABSTRACT: Methyl-1-phenylethylamines were resolved by phenylethylamine derivatives formed with a homologous series of dicarboxylic acids. The structure of the 4-methyl-1-phenylethylamine N-(1-phenylethylamine) succinic acid monoamide diastereoisomeric salt was investigated by single crystal X-ray diffraction.
[show abstract][hide abstract] ABSTRACT: Thermochemical properties of crown ether complexes have been studied by simultaneous TG-DTA (thermogravimetric analysis-differential
thermal analysis) coupled with a mass spectrometer, DSC (differential scanning calorimetry) and hot stage microscopy (HSM).
The examined complexes contain benzylammonium- [BA], (R)-(+)-a-phenylethylammonium- [(R)-PEA], (R)-(+)- and (S)-(-)-a-(1-naphthyl)ethylammonium perchlorate [(R)-NEA and (S)-NEA] salts as guests. In the cases of BA and (R)-PEA an achiral pyridono-18-crown-6 ligand [P18C6], and in the case of (R)-NEA and (S)-NEA a chiral (R,R)-dimethylphenazino-18-crown-6 ligand [(R,R)-DMPh18C6] was used as host molecule to obtain four different crown ether complexes. In all cases, the melting points of
the complexes were higher than those of both the host and the guest compounds. The decomposition of the complexes begins immediately
after their melting is completed, while the BA and (R)-PEA salts and the crown ether ligands are thermally stable by 50 to 100 K above their melting points. During the decomposition
of the salts and the four complexes strongly exothermic processes can be observed which are due to oxidative reactions of
the perchlorate anion. Ammonium perchlorate crystals were identified among the decomposition residues of the salts. P18C6
was observed to crystallize with two molecules of water. The studied complexes of P18C6 did not contain any solvate. BA was
observed to exhibit a reversible solid-solid phase transition upon heating. The heterochiral complex consisting of (S)-NEA and (R,R)-DMPh18C6 shows a solid-solid phase transition followed by two melting points. HSM observations identified three crystal
modifications, two of them simultaneously co-existing.
Journal of Thermal Analysis and Calorimetry 01/2004; 78(2):449-459. · 1.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Thermal treatment of torasemide form A resulted in several effects which were divided into five steps. These were investigated
and discussed applying TG-MS and TG-FTIR with additional information derived from SEM, hot-stage and FTIR microscopy. The
investigated crystal form of torasemide represents a mixed solvate including ethanol and water. Its desolvation, the solid-solid
transformation into the anhydrate mod. II and the melting of this anhydrate is elucidated using thermal analysis and microscopic
observations (FTIR and hot-stage microscopy). The released and evaporated solvents were determined with coupled techniques.
On further heating the structural identification of evolved gases allowed the analysis of the degradation pathway of torasemide
up to 340°C.
Journal of Thermal Analysis and Calorimetry 07/2003; 73(2):519-526. · 1.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Central adrenoceptors cannot currently be studied by PET neuroimaging due to a lack of appropriate radioligands. The fast-acting antidepressant drug mirtazapine, radiolabelled for PET, may be of value for assessing central adrenoceptors, provided that the radiation dosimetry of the radioligand is acceptable. To obtain that information, serial whole-body images were made for up to 70 min following intravenous injection of 326 and 185 MBq [N-methyl-11C]mirtazapine (specific activities E.O.S. of 119 and 39G Bq/micromol, respectively) in a healthy volunteer. Ten source organs plus remaining body were considered in estimating absorbed radiation doses calculated using MIRD 3.1. The highest absorbed organ doses were found to the lungs (3.4 x 10(-2) mGy/MBq), adrenals (1.2 x 10(-2) mGy/MBq), spleen (1.2 x 10(-2) mGy/MBq), and gallbladder wall (1.1 x 10(-2) mGy/MBq). The effective dose was estimated to be 6.8 x 10(-3) mSv/MBq, which is similar to that produced by several radioligands used routinely for neuroimaging.
Applied Radiation and Isotopes 01/2003; 59(2-3):175-9. · 1.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: O,O'-di-p-toluoyl-(2R,3R)-tartaric acid (DPTTA) was investigated as supramolecular complex (SMC) forming resolving agent with three racemic alcohols
(menthol, 4-methyl-2-pentanol, trans-2-iodo-cyclohexanol) by preparative scale experiments and thermoanalytical measurements.
Despite the very small structural difference (two methyl groups) between the O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) and DPTTA, their SMC forming properties with water and racemic alcohols is very different. While DBTA
forms SMC with all the three investigated alcohols, DPTTA forms SMC only with trans-2-iodo-cyclohexanol. DPTTA binds the guest compound less strongly and the stoichiometry of the SMC is also different. The
weaker interactions resulted in less effective optical resolutions. The results of these investigations remind us, that in
optical resolutions during the chiral discrimination process the weaker interactions have a determining role, since DBTA and
DPTTA have the possibility to form the same strong (O-HO and N-HO) hydrogen bond network.
Journal of Thermal Analysis and Calorimetry 01/2003; 74(1):155-162. · 1.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: We radiolabelled mirtazapine, a tetracyclic, atypical, antidepressant drug, for positron emission tomography (PET) and evaluated its regional kinetics in the living porcine brain. We produced [N-methyl-11C]mirtazapine with a radiochemical-purity >98% in a 21% decay-corrected radiochemical yield by alkylation of N-desmethyl mirtazapine with [11C]methyl iodide, followed by HPLC purification and formulation. [N-Methyl-11C]mirtazapine entered the brain readily and, under baseline conditions, it had an apparent volume of distribution (V(e)') of 9-13 in the basal ganglia, thalamus, and frontal cortex. Reference region and graphical analyses based on a one-compartment model showed that the binding of [N-methyl-11C]mirtazapine was reversible, with an apparent binding potential of more than two in thalamus and frontal cortex. Infusion of unlabelled mirtazapine markedly displaced [N-methyl-11C]mirtazapine from binding sites in the basal ganglia, thalamus and frontal cortex, but not in reference regions (cerebellum and olfactory tubercle). Thus, [N-methyl-11C]mirtazapine showed rapid passage into the living brain, slow metabolism in blood, and reversible, competitive binding, which may make it useful for PET neuroimaging of neuroreceptors involved in antidepressant actions.
European Neuropsychopharmacology 11/2002; 12(5):427-32. · 4.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: We synthesized [N-methyl-11C]mianserin by alkylation of N-desmethyl mianserin with [11C]methyl iodide followed by HPLC purification. We used PET for determining the regional cerebral pharmacokinetics of the radiotracer in anesthetized swine. [N-methyl-11C]Mianserin entered most brain regions readily (range of K1 values: 0.66-1.13), reaching highest levels in the basal ganglia and thalamus. The binding potential of [N-methyl-11C]mianserin was relatively low (range: 0.07-0.50), but regional differences were nonetheless observed, with highest values in the temporal cortex and lowest values in the brainstem. These PET findings, which are the first ones for a tetracyclic, antidepressant drug, show that [N-methyl-11C]mianserin has only a limited degree of regional specificity of binding in the living brain.
Nuclear Medicine and Biology 05/2002; 29(3):317-9. · 2.52 Impact Factor