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PubMedDate not supplied

In vitro organogenesis and alkaloid accumulation in Datura innoxia.

The kinetics of tropane alkaloids accumulation in different organs such as roots, leaves, stems, flowers and seeds of Datura innoxia was investigated by GC-MS. Twenty-six tropane alkaloids were detected. The ester derivatives of tropine (3alpha-tigloyloxytropine and 3-tigloyloxy-6-hydroxytropine) are the major compounds. Undifferentiated callus were established from the stem explants of Datura innoxia using Murashige and Skoog (MS) medium supplied with 6-benzylaminopurine (BA, 1 mg l(-10) and indole-3-acetic acid (IAA, 0.5 mg l(-1)) in combination for 6 weeks. Callus differentiation was initiated by subculture onto solid MS medium, free from hormones, for more than 10 months. Initially, shoots were formed after four weeks from subculture. Further subculturing in basal MS medium without growth regulators initiated the rooting of a shooty callus after 6 weeks. Investigation of the alkaloid content of the unorganized and organized callus revealed that callus (either green or brown) yielded only trace amounts of alkaloids. On the other hand, re-differentiated shoots contained mainly scopolamine while re-differentiated roots biosynthesized hyoscyamine as the main alkaloid.

Alkaloids↗
PubMedDate not supplied

The metabolic disposition of [14C]pivhydrazine, [14C]mebanazine, and [14C]benzylhydrazine in the rat.

The hydrazine drugs, [14C]pivhydrazine and [14C]mebanazine and the related compound [14C]benzylhydrazine were readily absorbed from the rat gut and the radioactivity was excreted mainly in urine. The major urinary metabolite of pivhydrazine and benzylhydrazine was [14C]hippuric acid, whereas mebanazine was shown to be excreted largely unchanged. Biliary excretion (21 and 24%, respectively) of radioactive material was observed after administration of [14C]pivhydrazine and [14C]mebanazine to bile duct-cannulated rats but only small amounts (approximately 3%) were excreted in bile after [14C]benzylhydrazine administration. The major biliary metabolites of pivhydrazine and mebanazine are acid-labile conjugates, possibly N-glucuronides. In vitro studies with rat liver homogenate suggest that benzylhyrazine may be an intermediate in the metabolism of pivhydrazine. The distribution of radioactivity in the rat 7 days after the administration of [14C]pivhydrazine and [14C]pivhydrazine and [14C]mebanazine is described.

Animals↗
PubMed2003

Influence of 2,5-dihydroxybenzylidene aminoguanidine on lipid oxidative damage and on antioxidant levels in model diabetes mellitus.

2,5-Dihydroxybenzylidene aminoguanidine (BAG) is a structural analogue of the antidiabetic compound aminoguanidine, and is an example of a substance protecting diabetic rats from lipoprotein oxidation arising in oxidative stress conditions characteristic of diabetes mellitus. We found that administration of BAG to diabetic rats decreases their susceptibility to lipoprotein oxidation, decreases formation of conjugated dienes and 4-hydroxy-2-nonenal, and increases antioxidant potential of plasma. On the other hand, our results show that BAG has a negative influence on lipoprotein oxidation in control rats. Increased formation of 4-hydroxy-2-nonenal and conjugated dienes and a decrease in plasma antioxidant potential was observed when BAG was administered to control rats. It is therefore necessary to search for other structural modifications of this substance that would combine higher antidiabetic activity with less toxicity in healthy individuals.

Aldehydes↗
PubMed2002

Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists.

A new class of potent dopamine D(4) antagonists was discovered with selectivity over dopamine D(2) and the alpha-1 adrenoceptor. The lead compound was discovered by screening our compound collection. The structure-activity relationships of substituted isoindoline rings and the chirality about the hydroxymethyl side chain were explored. The isoindoline analogues showed modest differences in potency and selectivity. The S enantiomer proved to be the more potent enantiomer at the D(4) receptor. Several analogues with greater than 100-fold selectivity for D(4) over D(2) and the alpha-1 adrenoreceptor were discovered. Several selective analogues were active in vivo upon oral or intraperitoneal administration. A chiral synthesis starting from either D- or L-O-benzylserine is also described.

Administration, Oral↗
PubMed1989

The inhibition of 5-lipoxygenase by RG 6866.

The generation of leukotrienes C4, D4 and E4 from arachidonic acid is dependent upon the activity of 5-lipoxygenase (5-LOX). The effects of RG 6866 (N-methyl-4-benzyloxyphenylacetohydroxamic acid) on the activity of guinea pig 5-LOX in vitro and in vivo were determined in the present study. The generation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) from arachidonic acid by isolated guinea pig peritoneal polymorphonuclear (PMN) cells was inhibited by incubation with RG 6866 (IC50 = 0.20 microM). A similar effect (IC50 = 0.23 microM) was observed when 5-HETE production was measured in a supernatant fraction from PMNs. Additionally, the compound did not inhibit 3H-LTD4 binding to guinea pig membranes. In actively sensitized guinea pigs pretreated with indomethacin, propranolol and pyrilamine, RG 6866 inhibited antigen-induced systemic anaphylaxis and LTD4-dependent bronchoconstriction in a dose-dependent manner following oral administration. In the pulmonary anaphylaxis model, significant (p less than 0.05) inhibition of the mortality was observed within 30 min and maintained through four hours after treatment with RG 6866 (50 mg/kg i.g.). Finally, orally administered RG 6866 inhibited the formation of LTC4 in these animals with an ED50 = 24.0 mg/kg. These findings indicate that RG 6866 is an inhibitor of 5-LOX both in vitro and in vivo.

Airway Resistance↗
PubMed1972

Distribution and excretion of N-( 14 C)-methyl labelled m-hydroxybenzyltrimethylammonium ions in mice.

1. Radioactivity in the plasma, livers, and brains of mice was measured at intervals of 10 min to 24 h after the intraperitoneal injection of (14)C labelled m-methoxy- and m-hydroxy- benzyltrimethylammonium ions.2. Well over 10% of the dose of either of these quaternary compounds was found in the liver and plasma within 10 min of the injection, but they were rapidly excreted or metabolized, having a half life of between 1 and 2 hours.3. Small amounts of radioactivity were detectable in brain, and were not due to contamination of brain samples by blood, after doses of 14-16 mumol/kg (approximately 4 mg iodide/kg) and upwards. After doses of 4-6 mumol/kg (approximately 1 mg iodide/kg), however, radioactivity in the brain was barely detectable.4. Any behavioural effects reported to occur in mice treated with these lower doses of m-hydroxybenzyltrimethylammonium, which include improved performance in a test of avoidance learning, are unlikely to be due to an action within the central nervous system. Learning may be more influenced by the peripheral effects of drugs than has hitherto been appreciated.

Animals↗
PubMed2005

In vitro properties of 5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone: a novel permeability transition pore inhibitor.

Despite the increasing implication of the permeability transition pore (PTP) in the pathophysiology of neurodegenerative diseases, few selective PTP inhibitors have been reported so far. Here, we evaluate the pharmacological properties of a novel PTP inhibitor, BBMP (5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone). This drug was discovered from the screening of a compound library against the PTP using a functional assay with isolated mitochondria. Similarly to cyclosporin A, the drug prevented Ca2+-induced permeability transition and mitochondrial depolarization. BBMP appeared more potent that minocycline in both swelling and membrane potential assays displaying pIC50 values of 5.5+/-0.1 and 5.6+/-0.0, respectively. Unlike minocycline, BBMP dose-dependently prevented DNA fragmentation induced by KCl 25/5 mM shift and serum deprivation in cerebellar granule neurons with a pIC50 of 5.7+/-0.6. The inhibition of PTP-mediated cytochrome c release observed in isolated mitochondria at 10 and 100 microM may explain its neuroprotective properties in vitro. These data suggest that the mitochondrial PTP is potentially involved in neuronal cell death and that PTP inhibitors, like BBMP, may possess a therapeutic potential in neurodegenerative disorders.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Dibenzyl sulfide metabolism by white rot fungi.

Microbial metabolism of organosulfur compounds is of interest in the petroleum industry for in-field viscosity reduction and desulfurization. Here, dibenzyl sulfide (DBS) metabolism in white rot fungi was studied. Trametes trogii UAMH 8156, Trametes hirsuta UAMH 8165, Phanerochaete chrysosporium ATCC 24725, Trametes versicolor IFO 30340 (formerly Coriolus sp.), and Tyromyces palustris IFO 30339 all oxidized DBS to dibenzyl sulfoxide prior to oxidation to dibenzyl sulfone. The cytochrome P-450 inhibitor 1-aminobenzotriazole eliminated dibenzyl sulfoxide oxidation. Laccase activity (0.15 U/ml) was detected in the Trametes cultures, and concentrated culture supernatant and pure laccase catalyzed DBS oxidation to dibenzyl sulfoxide more efficiently in the presence of 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonate) (ABTS) than in its absence. These data suggest that the first oxidation step is catalyzed by extracellular enzymes but that subsequent metabolism is cytochrome P-450 mediated.

Basidiomycota↗
PubMed1998

Enantiomeric inhibitors of cholesterol esterase and acetylcholinesterase.

Enantiomers of N-methyl-N,alpha-methylbenzylbutyramide (1), 1-butyl-3-methyl-3'-alpha-methylbenzylurea (2), 1,2,3, 4-tetrahydro-1-naphthyl-N-butylcarbamate (3), 1,1'-bi-2-naphthyl-2, 2'-di-N-butylcarbamate (4), 1, 1'-bi-2-naphthyl-2-ol-2'-N-butylcarbamate (5), and 1, 1'-bi-2-naphthyl-2-butyrate-2'-N-butylcarbamate (6) are inhibitors of porcine pancreatic cholesterol esterase-catalyzed hydrolysis of 4-nitrophenyl butyrate and of electric eel acetylcholinesterase-catalyzed hydrolysis of acetylthiocholine in the presence of 5,5'-dithiobis-2-nitrobenzoate. For competitive inhibitors, values of the inhibition constant (Ki) and the enantiomeric ratio (Ecomp.) are investigated. For active site-directed irreversible inhibitors, values of the inhibition constant (Ki), the carbamylation constant (k2), the bimolecular rate constant (ki), and the enantiomeric ratio (E) are investigated. Toward both enzymes, compounds 1 are poor competitive inhibitors (Ki=102-104 microM) but have good enantioselectivities (Ecomp.=10-50, the preference for R). R-2 and S-2 are competitive inhibitors of acetylcholinesterase with Ki=26 and 80 microM, respectively (the preference for R) but are active site-directed irreversible inhibitors of cholesterol esterase with ki=4 and 16 M-1 sec-1, respectively (the preference for S). For those competitive inhibitions, both leaving group hydrophilic and hydrophobic binding sites of cholesterol esterase or both anionic substrate binding site and peripheral anionic binding site of acetylcholinesterase bind to N,N-methyl-alpha-methylbenzyl disubstituted amide parts of these inhibitors and the enzyme does not catalyze the hydrolysis of these inhibitors. The opposite stereopreference (S) for the inhibition of cholesterol esterase by compounds 2 may be due to the fact that N, N-methyl-alpha-methylbenzyl disubstituted amide parts of these inhibitors bind to the alkyl chain binding site of the enzyme. Compounds 3-6 are active site-directed irreversible inhibitors of cholesterol esterase (ki=1-13000 M-1 s-1) and peripheral anionic binding site-directed irreversible inhibitors of acetylcholinesterase (ki=1.7-1300 M-1 s-1). Compounds 3 have low enantioselectivities (E=1.3-1.4) for both enzymes. The stereopreference for atropisomers 4 and 6 is S-form toward both enzymes (E=2-30) and is identical to that of cholesterol esterase-catalyzed hydrolysis of 1,1'-bi-2-naphthyl-2,2'-diacylate. This stereopreference (S) may be due to the fact that the butyryl group or one of two butylcarbamate groups of S-atropisomers binds more effectively to the leaving group hydrophobic binding site of cholesterol esterase or the peripheral anionic binding site of acetylcholinesterase than that of R-atropisomers. The opposite stereopreference (R) for atropisomers 5 toward both enzymes may be due to a favorable interaction between the hydroxyl group of the inhibitors and the leaving group hydrophilic binding site of cholesterol esterase or the peripheral anionic binding site of acetylcholinesterase.

Acetylcholinesterase↗
PubMed1995

Metabolic pathways of 4-[(3-methoxyphenyl)methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane (MPSC) hydrochloride, a silicon-containing xenobiotic, in rat, dog, and man.

1. The metabolic pathways of Sandoz compound 58-112, 4-[(3-methyoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane (MPSC) hydrochloride were evaluated in rat, dog, and man after a single oral dose. 2. In rat, dog and man the major route of elimination was renal. In the dog, renal excretion of unchanged MPSC represented a substantial portion of the dose whereas in rat and man MPSC was completely metabolized prior to excretion. 3. In rat and man, the major end-product metabolite was 3'-[((hydroxydimethylsilyl)-methylamino)methyl]-phenol glucuronide; 4-[(3-hydroxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane and 4-[(4-hydroxy-3-methoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2 ,6- disilacyclohexane and their conjugates were also present. In dog, the major end-product metabolites were the hippurate of 3-methoxybenzoic acid and 3-hydroxybenzoic acid.

Animals↗
PubMed1989

[The pharmacokinetic study of 3H-alpha-2-butylhydroxybenzyl alcohol in rabbits].

A derivative of Gastrodigenin, alpha-2-butylhydroxybenzyl alcohol, has shown a high distribution in the mice brain and stronger pharmacologic effects than its parent compounds. With 3H-alpha-2-butylhydroxybenzyl alcohol as radioactive tracer, pharmacokinetic data were obtained after the intravenous administration of a single dose alpha-2-butylhydroxybenzyl alcohol to rabbits, according to a cross-over design. Then, serial plasma samples were taken from 1 min to 480 min and measured by liquid scintillation counter. The data were analyzed by IBMPC computer for the estimation of pharmacokinetic parameters and the judgement of compartment model with a program recently developed by ourselves. The results suggested that the pharmacokinetics of alpha-2-butylhydroxybenzyl alcohol accords with the two compartment open model based on either the comparison of the calculated theoretic value with measured concentration or F test for the model judgement, and that the process of distribution was quite rapid, and the elimination half-life (T1/2 beta) was 12 h, indicating a slow elimination process.

Animals↗
PubMed2006

Bis(2-hydroxybenzylidene)acetone, a potent inducer of the phase 2 response, causes apoptosis in mouse leukemia cells through a p53-independent, caspase-mediated pathway.

Bis(2-hydroxybenzylidene)acetone is a potent inducer of the phase 2 response through the Keap1-Nrf2-ARE pathway. This double Michael reaction acceptor reacts directly with Keap1, the sensor protein for inducers, leading to enhanced transcription of phase 2 genes and protection against oxidant and electrophile toxicities. In our efforts to identify potent chemoprotective agents, we found that in rapidly growing murine leukemia cells (L1210) low concentrations (in the submicromolar range) of bis(2-hydroxybenzylidene)acetone markedly increased the activities of NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) and glutathione reductase, and the levels of total glutathione, three markers of the phase 2 response. In contrast, at high concentrations (in the micromolar range) the same compound caused G2/M cell cycle arrest and apoptosis. Importantly, a mutant L1210 cell line (Y8), selected for resistance to deoxyadenosine and lacking expression of p53 protein, was considerably more sensitive to the apoptotic effects of bis(2-hydroxybenzylidene)acetone. When caspase activities were evaluated in cell-free extracts prepared from treated wild type or mutant L1210 cells, the activities of caspase-3, the terminal caspase in the cascade leading to apoptosis, and caspase-10 were found to be markedly elevated. The activities of other caspases measured, caspase-1, -6 and -8, were not appreciably affected. Thus, both induction of the phase 2 response and p53-independent, caspase-3-mediated apoptosis could act cooperatively in chemoprotection. The concentration-dependent differential effects on these two pathways should be carefully considered in mechanistic explanations and strategic designs.

Acetone↗
PubMed1974

Mode of action of chronotropic agents in cardiac Purkinje fibers. Does epinephrine act by directly modifying the external surface charge?

Hauswirth et al. (1968) proposed that epinephrine acts on i(KK2) by adding its own positive charge to the external membrane surface near the i(KK2) channel. This hypothesis was tested by using noncationic compounds, theophylline and R07-2956, which mimicked epinephrine's effects on pacemaker activity and on i(KK2). In maximally effective doses, theophylline or R07-2956 occluded the effect of epinephrine, indicating a shared final common mechanism. Since theophylline and R07-2956 are noncationic at pH 7.4, the common mechanism cannot be a direct change in external surface charge. On the contrary, epinephrine does not interfere with the voltage shift produced by La(+++), which is thought to modify the external surface charge. The results argue against the original hypothesis but leave open the possibility that an alteration in internal surface charge generates the observed voltage shift. The potency of theophylline and R07-2956 as phosphodiesterase inhibitors suggests that the final common mechanism begins with the elevation of intracellular cyclic AMP, leading to a saturable process which limits the voltage shift's magnitude. This hypothesis is used to generate dose-response curves describing the combined effects of epinephrine and theophylline, and these are compared with experimental data.

Animals↗
PubMed1993

6-substituted 3,4-benzocoumarins: a new structural class of inducers and inhibitors of CYP1A1-dependent activity.

A new synthetic route was utilized to prepare 6-substituted 3,4-benzocoumarins where the substituents were iodo, fluoro, trifluoromethyl, bromo, chloro, isopropyl, ethyl, t-butyl, methyl, hydrogen, amino, phenyl, or nitro; 3,4-naphthocoumarin was also synthesized. The relative affinities of these congeners for the aryl hydrocarbon (Ah) receptor were determined using rat hepatic cytosol and 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin ([3H]TCDD) as the radioligand. In addition, the Ah receptor agonist activity of the 6-substituted 3,4-benzocoumarins was determined from their concentration-dependent induction of ethoxyresorufin O-deethylase (EROD) activity. In contrast with many other structural classes of halogenated aromatics, there was not a correlation between the structure-binding versus structure induction relationships for the 6-substituted 3,4-benzocoumarins. These results suggested that some of these congeners may exhibit partial Ah receptor antagonist activities and this was investigated by determining the inhibitory effects of 6-substituted 3,4-benzocoumarins on TCDD-induced EROD activity in rat hepatoma H4II E cells in culture. Only four compounds (6-isopropyl, 6-phenyl, 6-fluoro, and 6-t-butyl) inhibited the TCDD-induced response (21.7 to 64.4% inhibition) and the mechanism of action of the most active inhibitor, 6-t-butyl-3,4-benzocoumarin, was further investigated. In contrast, with other partial Ah receptor antagonists such as alpha-naphthoflavone, cotreatment of rat hepatoma H4II E cells with 1 nM TCDD plus 1 and 10 microM 6-t-butyl-3,4-benzocoumarin did not result in decreased levels of the Ah receptor complex (liganded with TCDD). In addition, there was not significant inhibition of TCDD-induced CYP1A1 mRNA levels or protein as determined by Northern and Western blot analyses. The results suggest that 6-t-butyl-3,4-benzocoumarin or one of its metabolites is a post-translational inhibitor of CYP1A1-dependent enzyme (EROD) activity in this cell line and thus represents a novel Ah receptor-independent inhibition of CYP1A1.

Animals↗
PubMed2006

Dextran derivatives modulate collagen matrix organization in dermal equivalent.

Dextran derivatives can protect heparin binding growth factor implied in wound healing, such as transforming growth factor-beta1 (TGF-beta1) and fibroblast growth factor-2 (FGF-2). The first aim of this study was to investigate the effect of these compounds on human dermal fibroblasts in culture with or without TGF-beta1. Several dextran derivatives obtained by substitution of methylcarboxylate (MC), benzylamide (B) and sulphate (Su) groups were used to determine the effects of each compound on fibroblast growth in vitro. The data indicate that sulphate groups are essential to act on the fibroblast proliferation. The dextran derivative LS21 DMCBSu has been chosen to investigate its effect on dermal wound healing process. Fibroblasts cultured in collagenous matrices named dermal equivalent were treated with the bioactive polymer alone or associated to TGF-beta1 or FGF-2. Cross-sections of dermal equivalent observed by histology or immunohistochemistry, demonstrated that the bioactive polymer accelerates the collagen matrices organization and stimulates the human type-III collagen expression. This bioactive polymer induces apoptosis of myofibroblast, property which may be beneficial in treatment of hypertrophic scar. Culture media analyzed by zymography and Western blot showed that this polymer significantly increases the secretion of zymogen and active form of matrix metalloproteinase-2 (MMP-2), involved in granulation tissue formation. These data suggest that this bioactive polymer has properties which may be beneficial in the treatment of wound healing.

Actins↗
PubMed1994

Genotoxicity of the alkenylbenzenes alpha- and beta-asarone, myristicin and elimicin as determined by the UDS assay in cultured rat hepatocytes.

While the alkenylbenzenes alpha- and beta-asarone are hepatocarcinogenic in rodents, myristicin and elimicin, two other alkenylbenzenes, are not. The present study investigated the mechanism of genotoxicity of the asarones to elucidate the role of cytochrome P-450 and obtain further information about the relationships between the structure, metabolism and genotoxicity of the alkenylbenzenes. The data on the ability of these compounds to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats are presented in this paper. Cytotoxicity was assessed by lactate dehydrogenase leakage. Elimicin and alpha- and beta-asarone are genotoxic in the UDS assay but myristicin is not. The genotoxicity of the asarones is inhibited by the cytochrome P-450 inhibitor cimetidine but the sulfotransferase inhibitor pentachlorophenol (PCP) is without effect. The major metabolite of the asarones in hepatocytes was identified by liquid chromatography-mass spectrometry as 2,4,5-trimethoxycinnamic acid but this was not genotoxic when tested separately. Simple allylbenzenes such as safrole, estragole and methyleugenol are activated by sequential 1-hydroxylation and sulfation, and this is the likely mechanism of the genotoxicity of elimicin. The propenyl analogues isosafrole, anethole and methylisoeugenol, which cannot undergo 1-hydroxylation, are not genotoxic. The positive results obtained with the asarones suggest the occurrence of a novel activation 'option' for alkenylbenzenes which features a 2-methoxy group in the aromatic ring.

Alkylation↗
PubMed2005

Myristicin-induced neurotoxicity in human neuroblastoma SK-N-SH cells.

Myristicin, 1-allyl-3,4-methylenedioxy-5-methoxybenzene, is a naturally occurring alkenylbenzene compound found in the nutmeg. The present study was conducted to assess the cytotoxic and apoptotic effects of myristicin on the human neuroblastoma SK-N-SH cells. We found that a dose-dependent reduction in cell viability occurs at myristicin concentration > or =0.5 mM in SK-N-SH cells. Apoptotic cell death was confirmed using DNA fragmentation, terminal deoxyribonucelotidyl transferase-mediated dUTP nick end labeling and by 4,6-diamidino-2-phenylindole staining. Microscopy was used to observe apoptotic cell morphology. Western blotting was used to investigate the protein expression of known apoptotic mediators including cytochrome c, caspase-3, and PARP. The apoptosis triggered by myristicin was accompanied by an accumulation of cytochrome c and by the activation of caspase-3. The results obtained suggest that myristicin induces cytotoxicity in human neuroblastoma SK-N-SH cells by an apoptotic mechanism. This myristicin-induced apoptosis provides further insight of the molecular mechanisms of myristicin toxicity.

Allylbenzene Derivatives↗
PubMed2000

Synthesis, (18)F-labeling, and biological evaluation of piperidyl and pyrrolidyl benzilates as in vivo ligands for muscarinic acetylcholine receptors.

A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, K(i) = 12.1 nM) and N-(2-fluoroethyl)-4-piperidyl benzilate (4-FEPB, 8, K(i) = 1. 83 nM) were selected for radiolabeling with fluorine-18. Using alkylation with 2-[(18)F]fluoroethyl triflate, 3-[(18)F]FEPB (42) and 4-[(18)F]FEPB (43) were produced in 7-9% radiochemical yield and >97% radiochemical purity. For in vivo studies, retention was moderate in mouse brain for 42; however, blocking with scopolamine showed that uptake was not muscarinic cholinergic receptor-mediated. Conversely, 43 exhibited high, receptor-mediated retention in mouse brain, with significant clearance after 1 h. These results suggest that 43 could have applications as an in vivo probe for measuring endogenous acetylcholine levels.

Acetylcholine↗