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At least 19 recordsLinked to original sources
PubMed2001

Evaluation of PET ligands (+)N-[(11)C]ethyl-3-piperidyl benzilate and (+)N-[(11)C]propyl-3-piperidyl benzilate for muscarinic cholinergic receptors: a PET study with microdialysis in comparison with (+)N-[(11)C]methyl-3-piperidyl benzilate in the conscious monkey brain.

We developed PET ligands (+)N-[(11)C]ethyl-3-piperidyl benzilate ([(11)C](+)3-EPB) and (+)N-[(11)C]propyl-3-piperidyl benzilate ([(11)C](+)3-PPB) for cerebral muscarinic cholinergic receptors. The distribution and kinetics of the novel ligands were evaluated for comparison with the previously reported ligand (+)N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB) in the monkey brain (Macaca mulatta) in the conscious state using high-resolution positron emission tomography (PET). At 60-91 min postinjection, regional distribution patterns of these three ligands were almost identical, and were consistent with the muscarinic receptor density in the brain as previously reported in vitro. However, the time-activity curves of [(11)C](+)3-EPB and [(11)C](+)3-PPB showed earlier peak times of radioactivity and a faster clearance rate than [(11)C](+)3-MPB in cortical regions rich in the receptors. Kinetic analysis using the three-compartment model with time-activity curves of radioactivity in metabolite-corrected arterial plasma as input functions revealed that labeling with longer [(11)C]alkyl chain length induced lower binding potential (BP = k(3)/k(4)), consistent with the rank order of affinity of these ligands obtained by an in vitro assay using rat brain slices and [(3)H]QNB. The cholinesterase inhibitor Aricept administered at doses of 50 and 250 microg/kg increased acetylcholine level in extracellular fluid of the frontal cortex and the binding of [(11)C](+)3-PPB with the lowest affinity to the receptors was displaced by the endogenous acetylcholine induced by cholinesterase inhibition, while [(11)C](+)3-MPB with the highest affinity was not significantly affected. Taken together, these observations indicate that the increase in [(11)C]alkyl chain length could alter the kinetic properties of conventional receptor ligands for PET by reducing the affinity to receptors, which might make it possible to assess the interaction between endogenous neurotransmitters and ligand-receptor binding in vivo as measured by PET.

Animals↗
PubMed2000

Development and evaluation of muscarinic cholinergic receptor ligands N-[11C]ethyl-4-piperidyl benzilate and N-[11C]propyl-4-piperidyl benzilate: a PET study in comparison with N-[11C]methyl-4-piperidyl benzilate in the conscious monkey brain.

The muscarinic cholinergic receptor ligands N-[(11)C]ethyl-4-piperidyl benzilate (4-EPB) and N-[(11)C]propyl-4-piperidyl benzilate (4-PPB) were developed and evaluated in comparison with N-[(11)C]methyl-4-piperidyl benzilate (4-MPB) in the conscious monkey brain using positron emission tomography (PET). Time-activity curves of [(11)C]4-EPB, unlike [(11)C]4-MPB, showed peaks within 91 min in regions rich in muscarinic receptors. [(11)C]4-PPB showed no specific binding even in the regions rich in these receptors. These observation demonstrated that increases in [(11)C]alkyl chain length could alter the kinetic properties of receptor ligands for PET.

Animals↗
PubMed1985

Binding of N-[propionyl-3H]propionylated alpha-bungarotoxin and L-[benzilic-4,4'-3H] quinuclidinyl benzilate to CNS extracts of the cockroach Periplaneta americana.

The nerve cord of the cockroach (Periplaneta americana) contains distinct saturable components of specific binding for the ligands N-[propionyl-3H]propionylated alpha-bungarotoxin and L-[benzilic-4,4'-3H]quinuclidinyl benzilate. N-[Propionyl-3H]propionylated alpha-bungarotoxin bound reversibly to homogenates with a Kd of 4.8 nM and Bmax of 910 fmol mg-1. The association rate constant (1.9 X 10(5) M-1 s-1) and dissociation rate constant (1.2 X 10(-4) s-1) yielded a Kd of 0.6 nM. Nicotinic ligands were found to displace toxin binding most effectively. The binding sites characterized in this way showed many similarities with the properties of the vertebrate neuronal alpha-bungarotoxin binding site. For a range of cholinergic ligands, inhibition constants calculated from toxin binding studies closely corresponded to their effectiveness in blocking the depolarizing response to acetylcholine recorded by electrophysiological methods from an identified cockroach motoneurone. The N-[propionyl-3H]propionylated alpha-bungarotoxin binding component therefore appears to be a constituent of a functional CNS acetylcholine receptor. Binding of L-[benzilic-4,4'-3H]quinuclidinyl benzilate was reversible with a Kd of 8 nM and Bmax of 138 fmol mg-1, determined from equilibrium binding experiments. The Kd calculated from the association rate constant (2.4 X 10(5) M-1 s-1) and dissociation rate constant (1.3 X 10(-4) s-1) was 1.9 nM. Muscarinic ligands were the most potent inhibitors of quinuclidinyl benzilate binding. The characteristics of this binding site resembled those of vertebrate CNS muscarinic cholinergic receptors. In contrast with vertebrate CNS, the nerve cord of Periplaneta americana contains more (approximately X 7) alpha-bungarotoxin binding sites than quinuclidinyl benzilate binding sites.

Animals↗
PubMed1979

The distribution of the muscarinic acetylcholine receptor antagonists, quinuclidinyl benzilate and quinuclidinyl benzilate methiodide (both tritiated), in rat, guinea pig, and rabbit.

The distribution of [3H]quinuclidinyl benzilate and its methiodide salt was determined in rat, guinea pig, and rabbit. Accumulation in the myocardium of up to 2% of the injected dose per gram of tissue was obtained with both compounds, providing heart-to-blood ratios of approximately 30 and heart-to-lung ratios of approximately 4. The accumulation in the heart was blocked (89%) by preinjection of atropine. The distribution of tritium in rabbit heart corresponds to the muscarinic receptor densities determined in vitro. Calculation of the theoretical maximum for the bound-to-free ratio, based on in-vitro equilibrium binding isotherms, resulted in ratios in reasonable agreement with the experimental results. Because of the high accumulation in the heart with low serum concentration, we conclude that the methiodide salt of quinuclidinyl benzilate represents an ideal parent structure for the design of a receptor-binding gamma-emitting radiopharmaceutical for imaging of the myocardium.

Acetylcholine↗
PubMed1991

Binding kinetics of quinuclidinyl benzilate and methyl-quinuclidinyl benzilate enantiomers at neuronal (M1), cardiac (M2), and pancreatic (M3) muscarinic receptors.

We analyzed the competition kinetics of quinuclidinyl benzilate (QNB) and QNB methiodide enantiomers on human NB-OK1 neuroblastoma (M1), rat cardiac (M2), and rat pancreas (M3) muscarinic binding sites. The association rate constants of the four drugs depended on the receptor subtype studied and were lower with pancreas (M3) (1-9 x 10(5) M-1 sec-1) than with cardiac (M2) (1-5 x 10(6) M-1 sec-1) and NB-OK1 (M1) (1-5 x 10(6) M-1 sec-1) binding sites. At each receptor subtype, we observed no significant difference between the association rate constants of the R- and S-enantiomers of either QNB or QNB methiodide. Receptor stereoselectivity, when present, was associated with differences in unlabeled drug dissociation rate constants. The dissociation rate constant varied much more than the association rate constant, when either (R)-QNB dissociation from the three subtypes (half-life, 77 min to greater than 340 min; best fit, 40 days) or dissociation of the four drugs from each receptor subtype (half-lives varying from 1.4 min to 4 hr at M1 receptors, 1.1 to 77 min at M2 receptors, and 3.5 min to greater than 340 min at M3 receptors were obtained by competition kinetics analysis) was compared.

Animals↗
PubMed2006

A FMO-controlled reaction path in the benzil-benzilic acid rearrangement.

Reaction paths for the title rearrangement along with its methyl analogue were investigated by density functional theory calculations. The reaction model is R-CO-CO-R + OH(-)(H2O)4 --> R2C(OH)-COO- + (H2O)4 (R = Me and Ph), where the water tetramer is employed both for solvation to OH- and for the proton relay along hydrogen bonds. The reaction is composed of OH- addition, C-C rotation, carbanion [1,2] migration, and proton relay toward the product anions. The rate-determining step was calculated to be the carbanion migration. Apparently, carbanion [1,2] migration is unlikely relative to the carbonium ion one. However, LUMOs of the 1,2-diketones have large and nodeless lobes at the reaction center, the C1-C2 bond. The specific LUMO character is reflected both in the [2+1]-like one-center nucleophilic addition and in the carbanion [1,2] shift. The proton relay involved in the isomerization from the oxo intermediate to the carboxylate was calculated to take place via the water tetramer.

Journal Article↗
PubMed2002

The enzymes with benzil reductase activity conserved from bacteria to mammals.

The diketone compound, benzil is reduced to (S)-benzoin with living Bacillus cereus cells. Recently, we isolated a gene responsible for benzil reduction, and Escherichia coli cells in which this gene was overexpressed transformed benzil to (S)-benzoin. Although this benzil reductase showed high identity to the short-chain dehydrogenase/reductase (SDR) family, enzymological features were unknown. Here, we demonstrated that many B. cereus strains had benzil reductase activity in vivo, and that the benzil reductases shared 94-100% amino acid identities. Recombinant B. cereus benzil reductase produced optically pure (S)-benzoin with NADPH in vitro, and the ketone group distal to a benzene ring was asymmetrically reduced. B. cereus benzil reductase showed 31% amino acid identity to the yeast open reading frame YIR036C protein and 28-30% to mammalian sepiapterin reductases, sharing the seven residues consensus for the SDR family. We isolated the genes encoding yeast YIR036C protein and gerbil sepiapterin reductase, and both recombinant proteins also reduced benzil to (S)-benzoin in vitro. Green fluorescent protein-tagged B. cereus benzil reductase distributed in the bipolar cytoplasm in B. cereus cells. Asymmetric reduction with B. cereus benzil reductase, yeast YIR036C protein and gerbil sepiapterin reductase will be utilized to produce important chiral compounds.

Alcohol Oxidoreductases↗
PubMed2003

Multiple conformations of benzil in resorcinarene-based supramolecular host matrixes.

Six supramolecular complexes incorporating benzil as a guest, CMCR*bipy*benzil (alpha) 1 (CMCR = C-methylcalix[4]resorcinarene), CMCR*bipy*benzil (beta) 2, CMCR*2bpe*benzil*ethanol 3 (bpe = trans-1,4-bis(pyridyl)ethylene), CMCR*2bpe*benzil*2H2O 4, CMCR.2bpeh*benzil*ethanol 5 (bpeh = bis-(1-pyridin-4-yl-ethylidene)-hydrazine), and CECR*2bpe.benzil 6 (CECR = C-ethylcalix[4]resorcinarene), have been synthesized by hydrothermal and conventional methods and characterized by X-ray diffraction. Resorcinarene adopts a boat conformation in 1-4 and a bowl conformation in 5 and 6. Compounds 1-4 show a brick-wall-like framework, in which two benzil molecules are incorporated. For 5, bpeh spacers link CMCR molecules to give a one-dimensional wavelike polymer in which one benzil guest is embedded within the polymer cavity. Complex 6 forms a carcerand-like capsule in which two benzil guests are encapsulated. The O=C-C=O torsion angles vary from 91.8 to 139.3 degrees and correlate with the length of the central C-C bond. The benzil concentration, which is approximately 6.2 mol/L in the neat crystals, varies between 1.01 and 1.51 mol/L in the structures studied, corresponding to a 6-fold dilution. The benzil molecules are disordered in the larger cavities of 4 and 5. The two benzoyl fragments are almost perpendicular in 3, which has the next largest cavity size when solvent volume is excluded, whereas a nearly trans-coplanar conformation occurs for the cavity with the smallest volume in 6.

Journal Article↗
PubMedDate not supplied

[3H]tricyclopinate binding to brain muscarinic acetylcholine receptors: a comparison with [3H]quinuclidinyl benzilate.

The purpose of our study was to investigate the binding characteristics of a newly synthesized compound, tricyclopinate, at muscarinic acetylcholine receptors from rat cerebral cortex. This was achieved through the use of radiolabelled quinuclidinyl benzilate and radiolabelled tricyclopinate. Our data demonstrated that the saturation binding parameters of [3H]tricyclopinate (Kd = 0.10 nM, Bmax = 1056 fmol mg-1) were almost identical to those of [3H]quinuclidinyl benzilate (Kd = 0.11 nM, Bmax = 1022 fmol mg-1); both ligands fit a one site model of receptor-ligand interaction. Concentration-inhibition curves were used to determine Ki values for four antimuscarinic compounds. The rank order of potencies of the antagonists for displacement of the two ligands was: tricyclopinate = quinuclidinyl benzilate > atropine > pirenzepine. The competition binding parameters of [3H]tricyclopinate were similar to those of [3H]quinuclidinyl benzilate. The associate rate constants (Ki) were 0.25 and 0.21 nM-1 min-1 for [3H]tricyclopinate and [3H]quinuclidinyl benzilate, respectively. The dissociation of bound [3H]tricyclopinate from central muscarinic acetylcholine receptors was complete and was modified by the allosteric agent, gallamine. By comparison, only half of the bound [3H]quinuclidinyl benzilate was dissociated from muscarinic acetylcholine receptors and the dissociation of bound [3H]quinuclidinyl benzilate was not modified by gallamine. The dissociation rate constants (K-i) were 0.0325 and 0.0072 min-1 for [3H]tricyclopinate and [3H]quinuclidinyl benzilate, respectively. These results showed that the two ligands have different binding characteristics to muscarinic acetylcholine receptors. [3H]tricyclopinate should be very useful for further study of central muscarinic acetylcholine receptors; it might complement the use of [3H]N-methylscopolamine and [3H]quinuclidinyl benzilate in the study of muscarinic acetylcholine receptors.

Animals↗
PubMed1982

Muscarinic receptors on rat isolated colonic epithelial cells. A correlation between inhibition of [3H]quinuclidinyl benzilate binding and alteration in ion transport.

Muscarinic cholinergic agonists stimulate secretion or inhibit absorption in the large intestine both in vivo and in vitro, effects that are completely inhibited by atropine, a specific muscarinic antagonist. These studies were performed to determine if the muscarinic-induced alteration in electrolyte transport in rat colon was produced by muscarinic agonists binding directly to receptors on colonic enterocytes. We found that crude membranes prepared from rat isolated colonic epithelial cells had a specific, saturable, high affinity receptor for L-[benzilic-4,4-3H]quinuclidinyl benzilate, a potent muscarinic antagonist with an apparent dissociation coefficient of 0.56 +/- 0.11 nM and a maximum number of binding sites of 42.5 +/- 5.7 fmol/mg protein. Muscarinic antagonists inhibited L-[benzilic-4,4-3H]quinuclidinyl benzilate binding in nanomolar concentrations, and muscarinic agonists inhibited L-[benzilic-4,4-3H]quinuclidinyl benzilate binding in micromolar concentrations. In parallel studies, oxotremorine and bethanechol, muscarinic agonists, and racemic quinuclidinyl benzilate altered short-circuit current in rat colon in vitro in concentrations that were in good agreement with the concentrations that inhibited L-[benzilic-4,4-3H]quinuclidinyl benzilate binding to the crude membrane preparation. Thus, these studies demonstrate that the muscarinic-induced alteration in colonic electrolyte transport is directly related to agonist binding to a specific muscarinic receptor on the colonic epithelial cell.

Animals↗
PubMed2003

A diffuse reflectance comparative study of benzil inclusion within microcrystalline cellulose and beta-cyclodextrin.

Diffuse reflectance and laser-induced techniques were used to study photochemical and photophysical processes of benzil adsorbed on two solid powdered supports, microcrystalline cellulose and [small beta]-cyclodextrin. In both substrates, a distribution of ground-state benzil conformers exists, largely dominated by skew conformations where the carbonyl groups are twisted one to the other. Room temperature phosphorescence was observed in air-equilibrated samples in both cases. The decay times vary greatly and the largest lifetime was obtained for benzil/[small beta]-cyclodextrin, showing that this host's cavity accommodates benzil well, enhancing its room temperature phosphorescence. Triplet-triplet absorption of benzil entrapped in cellulose was detected and benzil ketyl radical formation also occurred. With benzil included into [small beta]-cyclodextrin, and following laser excitation, benzoyl radicals were detected on the millisecond timescale. Product analysis and identification of laser-irradiated benzil samples in the two hosts clearly showed that the main degradation photoproducts were benzoic acid and benzaldehyde. The main differences were a larger benzoic acid/benzaldehyde ratio in the case of cellulose and the formation of benzyl alcohol in this support.

Adsorption↗
PubMed2005

Enantiomeric N-methyl-4-piperidyl benzilates as muscarinic receptor ligands: Radioligand binding studies and docking studies to models of the three muscarinic receptors M1, M2 and M3.

Benzilic ester derivatives with a basic moiety like N-methyl-4-piperidyl benzilates are potential drugs for the treatment of urinary incontinence, duodenal and gastric ulcers and Parkinson's disease. The effect of structural variations of chiral N-methyl-4-piperidyl benzilates was investigated using radioligand binding studies on muscarinic receptors (M1-M3). The results of the binding studies demonstrate that the absolute configuration and the aromatic substituent of benzilates have an influence on muscarinic affinity and selectivity. In this regard, (S)-configuration of benzilates and hydrophilic aromatic substituents seems to enhance muscarinic affinity. A model of the receptor ligand complex for N-methyl-4-piperidyl benzilates was obtained by molecular modelling. Both the affinity of enantiomeric benzilic esters and the subtype selectivity for muscarinic receptors are comprehensively explained by this model.

Animals↗
PubMed1984

[3H]Pirenzepine and [3H]quinuclidinyl benzilate binding to brain muscarinic cholinergic receptors. Differences in measured receptor density are not explained by differences in receptor isomerization.

Muscarinic receptor densities were measured in membranes prepared from rat cerebral cortex using [3H]pirenzepine and [3H]quinuclidinyl benzilate. Isotherms of equilibrium binding data modeled to a single apparent binding site for both ligands. However, as has been reported previously, [3H]pirenzepine labeled only a small fraction of the binding sites that were labeled by [3H]quinuclidinyl benzilate. This observation has been used to support the hypothesis that subtypes of muscarinic receptors exist. Several investigators have previously suggested that antagonist binding to muscarinic receptors involves an isomerization of the receptor-antagonist complex, and it is only the isomerized form of the receptor that is identified by radioligand binding studies. To examine the possibility that the difference in the density of binding sites identified by [3H]pirenzepine and [3H]quinuclidinyl benzilate is due to differences in the degree of isomerization of the receptor associated with the binding of each ligand, the kinetics of the binding of [3H]pirenzepine and [3H]quinuclidinyl benzilate to membranes prepared from rat cerebral cortex were examined. The pseudo-first-order rate constant of association for both ligands showed a nonlinear (hyperbolic) dependence on ligand concentration. These results suggested that a rapidly equilibrating initial binding step was followed by a more slowly equilibrating isomerization of the initially formed ligand-receptor complex. The kinetic data were computer-modeled to obtain estimates of the equilibrium constants for both reaction steps. The equilibrium constants for the isomerization step were 0.1 and 0.004 for [3H]pirenzepine and [3H]quinuclidinyl benzilate, respectively. Our measurements, in agreement with others, suggested that only the fraction of receptors which isomerized were measurable using filtration binding assays. Although essentially all (99.6%) of the [3H]quinuclidinyl benzilate binding sites appeared to isomerize, only 90% of the [3H]pirenzepine binding sites isomerized, and thus only 90% were measured in our assay. It therefore appears that differences in receptor isomerization can partially, but not wholly, account for the differences between [3H]pirenzepine and [3H]quinuclidinyl benzilate binding in rat cerebral cortex.

Animals↗
PubMed2004

Sensitized phosphorescence of benzil-doped ladder-type methyl-poly(para-phenylene).

The delayed luminescence and phosphorescence of ladder-type methyl-poly(para-phenylene) (MeLPPP) doped with benzil at a concentration of 20% by weight has been measured. The introduction of benzil leads to a dramatic reduction of the polymer singlet emission. At the same time, a new band with maximum at 611 nm appears, corresponding to the phosphorescence of MeLPPP. The phosphorescence decay on the short time scale is close to an exponential law with a time decay of 15 ms. This indicates that benzil can efficiently sensitize the phosphorescence of the polymer. In addition, a broad and featureless emission is observed in the delayed luminescence spectra of benzil-doped MeLPPP, which is attributed to an exciplex formed between the polymer host and the dopant. We further observe that the delayed fluorescence is enhanced by the addition of benzil. It is concluded that the delayed fluorescence of benzil-doped MeLPPP is mainly due to the annihilation of triplet excitons on the polymer. Finally, efficient triplet-triplet energy transfer from the benzil-doped polymer to the red-emitting phosphorescent dye Pt(II)octaethylporphyrin is established.

Journal Article↗
PubMed1980

Benzil, a potent activator of microsomal epoxide hydrolase in vitro.

Benzil was found to be a very potent activator of microsomal epoxide hydrolase activity (measured with styrene oxide as substrate) in vitro. The activating effect was uncompetitive and benzil causes approximately ninefold increases in both the apparent V and the apparent Km of the enzyme(s). The half-maximal effect on activity was obtained as a 0.3 mM concentration of benzil. The activating effect obtained with benzil was found to be very specific, since a variety of structurally related compounds had little or no effect on microsomal epoxide hydrolase activity. In order to obtain indications for the existence of more than one microsomal epoxide hydrolase the effect of benzil on this activity from rats induced with phenobarbital, 3-methylcholanthrene, 2-acetylaminofluorene, trans-stilbene oxide, and benzil was tested. The differences observed were minor.

Aldehydes↗
PubMed2001

Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors.

The potential interaction of acetylcholinesterase inhibitors with cholinergic receptors may play a significant role in the therapeutic and/or side-effects associated with this class of compound. In the present study, the capacity of acetylcholinesterase inhibitors to interact with muscarinic receptors was assessed by their ability to displace both [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding in rat brain membranes. The [3H]-quinuclinidyl benzilate/[3H]-oxotremorine-M affinity ratios permitted predictions to be made of either the antagonist or agonist properties of the different compounds. A series of compounds, representative of the principal classes of acetylcholinesterase inhibitors, displaced [3H]-oxotremorine-M binding with high-to-moderate potency (ambenonium>neostigmine=pyridostigmine=tacrine>physostigmine> edrophonium=galanthamine>desoxypeganine) whereas only ambenonium and tacrine displaced [3H]-quinuclinidyl benzilate binding. Inhibitors such as desoxypeganine, parathion and gramine demonstrated negligible inhibition of the binding of both radioligands. Scatchard plots constructed from the inhibition of [3H]-oxotremorine-M binding in the absence and presence of different inhibitors showed an unaltered Bmax and a reduced affinity constant, indicative of potential competitive or allosteric mechanisms. The capacity of acetylcholinesterase inhibitors, with the exception of tacrine and ambenonium, to displace bound [3H]-oxotremorine-M in preference to [3H]quinuclinidyl benzilate predicts that the former compounds could act as potential agonists at muscarinic receptors. Moreover, the rank order for potency in inhibiting acetylcholinesterase (ambenonium>neostigmine=physostigmine =tacrine>pyridostigmine=edrophonium=galanthamine >desoxypeganine>parathion>gramine) indicated that the most effective inhibitors of acetylcholinesterase also displaced [3H]-oxotremorine-M to the greatest extent. The capacity of these inhibitors to displace [3H]-oxotremorine-M binding preclude their utilisation for the prevention of acetylcholine catabolism in rat brain membranes, the latter being required to estimate the binding of acetylcholine to [3H]-oxotremorine-M-labelled muscarinic receptors. However, fasciculin-2, a potent peptide inhibitor of acetylcholinesterase (IC50 24 nM), did prevent catabolism of acetylcholine in rat brain membranes with an atypical inhibition isotherm of [3H]-oxotremorine-M binding, thus permitting an estimation of the "global affinity" of acetylcholine (Ki 85 nM) for [3H]-oxotremorine-M-labelled muscarinic receptors in rat brain.

Animals↗
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↗