Optical resolution of 1-(1-naphthyl)ethylamine by its dicarboxylic acid derivatives: Structural features of the oxalic acid derivative diastereomeric salt pair.

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).

Enhanced efficiency due to the use of achiral additives in the optical resolution of 1-phenylethylamine by its glutaric acid derivative.

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.

Inhibition of [11C]mirtazapine binding by alpha2-adrenoceptor antagonists studied by positron emission tomography in living porcine brain.

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.

PET neuroimaging of [11C]mirtazapine enantiomers in pigs.

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.

[N-methyl-11C]Mirtazapine for positron emission tomography neuroimaging of antidepressant actions in humans.

RATIONALE: 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. OBJECTIVE: To determine the regional central biodistribution and pharmacokinetics of [N-methyl-11C]mirtazapine in humans. METHODS: Five healthy volunteers received an intravenous injection of [N-methyl-11C]mirtazapine for evaluating its metabolism, biodistribution and pharmacokinetics. RESULTS: [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). CONCLUSIONS: [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.

Morphological investigation of chemically treated poly(ethylene terephthalate)-based activated carbons.

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.

Biodistribution and radiation dosimetry of [N-methyl-11C]mirtazapine, an antidepressant affecting adrenoceptors.

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.

[11C]Mirtazapine for PET neuroimaging: radiosynthesis and initial evaluation in the living porcine brain.

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.