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At least 19 recordsLinked to original sources
PubMed1997

Synthesis and ligand binding of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4'-iodophenyl)nortropane and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-disubstituted phenyl)nortropane. New high-affinity and selective compounds for the dopamine transporter.

Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K(i) values of N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.

Animals↗
PubMed2003

6beta-acetoxy nortropane regulated processing of amyloid precursor protein in CHOm1 cells and rat brain.

The effects of the muscarinic receptor agonist 6beta-acetoxy nortropane on amyloid precursor protein (APP) processing were studied in both transfected Chinese hamster ovary cells stably expressing muscarinic M(1) receptors (denoted as CHOm(1) cell line) and in cerebral cortical and hippocampal slices. Exposure of CHOm(1) cells to 6beta-acetoxy nortropane for 1 h significantly increased the secretion of secretory amyloid precursor protein (derived from alpha-secretase cleavage) in a concentration-dependent manner. In the same system, 6beta-acetoxy nortropane reduced the beta-amyloid peptide production. Similar results were obtained in hippocampal and cerebral cortical slices, with 6beta-acetoxy nortropane administration resulting in an increase in secretory amyloid precursor protein and a decrease in beta-amyloid peptide release. The increase of secretory amyloid precursor protein secretion was abolished by preincubation with selective muscarinic M(1) receptor antagonist pirenzepine, but not by preincubation with selective muscarinic M(2) receptor antagonist methoctramine, suggesting that 6beta-acetoxy nortropane promotes secretory amyloid precursor protein release in the brain via muscarinic M(1) receptor activation. These results suggest that 6beta-acetoxy nortropane could exert a beneficial effect on the progress of Alzheimer's disease by promoting amyloid precursor protein processing through alpha-secretase.

Amyloid beta-Peptides↗
PubMed2003

Synthesis and characterization of iodine-123 labeled 2beta-carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane. A ligand for in vivo imaging of serotonin transporters by single-photon-emission tomography.

2beta-Carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and 2beta-carbomethoxy-3beta-(4'-((E)-2-iodoethenyl)phenyl)nortropane (EIENT) (10) were prepared and evaluated in vitro and in vivo for serotonin transporter (SERT) selectivity and specificity. High specific activity [(123)I]ZIENT and [(123)I]EIENT were synthesized in 45% (n = 5) and 42% (n = 4) radiochemical yield (decay-corrected to end of bombardment (EOB)), respectively, by preparation of the precursor carbomethoxy-3beta-(4'-((Z)-2-trimethylstannylethenyl)phenyl)nortropane (7) and 2beta-carbomethoxy-3beta-(4'-((E)-2-tributylstannylethenyl)phenyl)nortropane (9), respectively, followed by treatment with no carrier-added sodium [(123)I]iodide and hydrogen peroxide in ethanolic HCl. Competition binding in cells stably expressing the transfected human SERT, dopamine transporter (DAT), and norepinephrine transporter (NET) using [(3)H]citalopram, [(3)H]WIN 35,428, and [(3)H]nisoxetine, respectively, demonstrated the following order of SERT affinity (K(i) in nM): ZIENT (0.05) > nor-CIT (0.12) >> EIENT (1.15) > fluvoxamine (1.46). The affinity of ZIENT and EIENT for DAT was 69 and 1.6-fold lower, respectively, than for SERT. In vivo biodistribution and blocking studies were performed in male rats and demonstrated that the brain uptake of [(123)I]ZIENT was selective and specific for SERT-rich regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain imaging studies in monkeys demonstrated high [(123)I]ZIENT uptake in the diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190 min. [(123)I]ZIENT uptake in the diencephalon achieved transient equilibrium at 157 min. In a displacement experiment of [(123)I]ZIENT in a cynomolgus monkey, radioactivity was reduced by 39% in the diencephalon at 101 min following injection of citalopram. The high specific activity one-step radiolabeling preparation and high selectivity of [(123)I]ZIENT for SERT support its candidacy as a radioligand for mapping brain SERT sites.

Animals↗
PubMed1983

Synthesis and structural study of N-substituted nortropane spirohydantoins.

A series of N8-alkyloxycarbonylalkyl-nortropane-3-spiro-5'-hydantoins has been synthesized and studied by spectral and crystallographic methods. The crystal and molecular structure of one [8(gamma-ethoxycarbonyl)nortropane-3-spiro-5'-hydantoin, VI] was determined by X-ray diffraction. The preferred conformations of these compounds and subsequent changes on protonation were determined from 1H-NMR and 13C-NMR data.

Chemical Phenomena↗
PubMed1995

Iodine-123 labelled N-(2-fluoroethyl)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane for dopamine transporter imaging in the living human brain.

There are several cocaine analogs which have potential for imaging the dopamine transporters (DAT). Earlier studies have shown that iodine-123 labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT) and N-(3-fluoropropyl)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane ([123I]beta-CIT-FP) are promising DAT imaging agents in the living human brain with single-photon emission tomography (SPET). Here we report a pilot comparison of [123I]beta-CIT and [123I]beta-CIT-FP with a new tropane derivative, [123I]N-(2-fluoroethyl)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane ([123I]beta-CIT-FE), using SPET imaging in four healthy male subjects. Peak uptake of [123I]beta-CIT-FE into the basal ganglia occurred very rapidly (0.5 h after injection of tracer), after which the striatal washout obeyed a bi-exponential form. The specific DAT binding of [123I]beta-CIT-FE into the basal ganglia was somewhat less (0.785 +/- 0.117) than that of [123I]beta-CIT (0.922 +/- 0.004) or [123I]beta-CIT-FP (0.813 +/- 0.047). All these tracers have excellent imaging quality in healthy control subjects. However, the relatively fast washout of [123I]beta-CIT-FE and low temporal resolution of older SPET cameras may limit the use of this tracer to the measurement of the DAT density.

Adult↗
PubMed2000

3alpha-(4-Substituted phenyl)nortropane-2beta-carboxylic acid methyl esters show selective binding at the norepinephrine transporter.

A series of 3alpha-(4-substituted)nortropane-2beta-carboxylic acid methyl esters was synthesized and evaluated for the ability to inhibit radioligand binding at the dopamine, serotonin, and norepinephrine transporters. 3alpha-(4-Methylphenyl)nortropane-2beta-carboxylic acid methyl ester (4c) was found to be selective and highly potent for the norepinephrine transporter (NET) relative to the dopamine and serotonin transporters.

Carboxylic Acids↗
PubMed1999

Radiosynthesis of [18F] N-3-fluoropropyl-2-beta-carbomethoxy-3-beta (4' methylphenyl) nortropane (FPCMT).

A synthetic procedure for the routine preparation of [18F] N-3-fluoropropyl-2-beta-carbomethoxy-3-beta-(4' methylphenyl) nortropane (18F FPCMT) has been developed. The synthesis is based on alkylation of nortropane with 18F labeled fluoropropyl tosylate. Purification of the final product was achieved by a preparative HPLC procedure using Alltech Econosil column. Separation of the desired compound was achieved and the product was clean. The radiochemical yield (without decay correction) is 4 to 5%, calculated at the end of the synthesis based on the total amount of fluorine recovered from the target. Radiochemical purity was in the range of 98 to 99%.

Chromatography, High Pressure Liquid↗
PubMed1979

4-Anilidopiperidine analgesics. 2. A study of the conformational aspects of the analgesic activity of the 4-anilidopiperidines utilizing isomeric N-substituted 3-(propananilido)nortropane analogues.

Relatively little information is available concerning the influence of conformational factors on the potent analgesic actions of the 4-anilidopiperidines. A series of N-substituted 3 alpha- and 3 beta-(propananilido)nortropanes have been designed, synthesized, and stereochemically characterized as semirigid analogues of the 4-anilidopiperidine analgesics in an attempt to study the influence of certain stereochemical factors on analgesia in this class of compounds. Conformational analysis of 3 alpha-propananilides (4) reveals a boat conformation for the preferred conformation of the piperidine ring of these tropane analogues. Evaluation of the analgesic potencies of the isomeric N-substituted 3-(propananilido)nortropanes of this study indicates greater potency for the 3 beta-(propananilido) isomers (5) with N-benzyl and N-phenethyl substitution as compared to the corresponding N-substituted 3 alpha-propananilides. Analysis of relative solubility differences among these isomers suggests that both structural and stereochemical influences predominate in affecting analgesic potency.

Analgesics↗
PubMed2006

Evaluation of carbon-11-labeled 2beta-carbomethoxy-3beta-[4'-((Z)-2-iodoethenyl)phenyl]nortropane as a potential radioligand for imaging the serotonin transporter by PET.

The nortropane cocaine analogue, 2beta-carbomethoxy-3beta-[4'-((Z)-2-iodoethenyl)phenyl]nortropane (ZIENT), is a high affinity, selective serotonin transporter (SERT) ligand that has shown promise as a SERT imaging agent for single photon computed tomography (SPECT) when labeled with I-123. Synthesis of the labeling precursor, radiosynthesis of [(11)C]ZIENT, and in vivo evaluation in anesthetized and awake monkeys have been performed to determine the suitability of [(11)C]ZIENT as a PET agent for SERT imaging.

Animals↗
PubMed2006

Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography.

2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT.

Animals↗
PubMed1996

Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs.

New methods for the synthesis of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved coupling of the appropriate organometallic reagents to 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (6a, RTI-55) or to an N-protected derivative of 6a followed by N-demethylation or removal of the protecting group. Some analogs were prepared by catalytic reduction of the alkene and alkene analogs 3 and 4 or by isomerization of the alkenes 3. The analogs 2-4 were evaluated for inhibition of radioligand binding to the serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transporters. 3 beta-(4'-Isopropenyl- and 4'-cis-propenylphenyl)nortropane-2 beta-carboxylic acid methyl esters (3b,d), which possessed IC50 values of 0.6 and 1.15 nM, respectively, were the most potent analogs at the 5-HT transporter, and with NE/5-HT IC50 ratios of 240 and 128 nM, respectively, they were selective for the 5-HT relative to the NE transporter. Since interaction with the serotonin transporter may modulate the pharmacological effects resulting from binding to the dopamine transporter, 3 beta-(4'-isopropenylphenyl)tropane-2 beta-carboxylic acid methyl ester (11b) which has good affinity for both the 5-HT and DA transporters but low affinity at the NE transporter may be useful for studying this interaction.

Animals↗
PubMed2005

Pharmacological characterization of (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999) as a highly promising fluorinated ligand for the dopamine transporter.

In the aim to develop an efficient fluorinated probe for positron emission tomography (PET) exploration of the dopamine transporter (DAT), we studied several in vitro and in vivo characteristics of the phenyltropane derivative (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999). In vitro on rat striatal membrane, [(3)H]LBT-999 bound to a single site with a K(d) of 9 nM, B(max) of 17 pmol/mg protein, and a very high selectivity for the DAT [IC(50) for 1-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) and (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane (PE2I): 2.4 and 18 nM, respectively; IC(50) for paroxetine, citalopram, N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, nisoxetine, and desipramine >1 muM]. In vitro on post-mortem human brain sections, LBT-999 bound with high intensity to the caudate-putamen, weakly to the thalamus, and not in the neocortex and cerebellum. This binding was totally abolished in the presence of PE2I. Ex vivo cerebral biodistribution of [(11)C]LBT-999 in rats showed striatum/cerebellum radioactivity ratios of 18 and 25 at 30 and 60 min postinjection, respectively. This accumulation was strongly prevented by preinjection of GBR 12909, whereas paroxetine and nisoxetine had no effect. An in vivo kinetic PET study in three baboons showed a fast and very high uptake in the striatum, with a plateau at 30 min postinjection and a maximal putamen/cerebellum ratio of 30. Taken together, these findings demonstrate that LBT-999 is a highly promising agent for in vivo exploration of the DAT. This probe is currently labeled with (18)F for further characterizations.

Animals↗
PubMed2001

Synthesis of tropane and nortropane analogues with phenyl substitutions as serotonin transporter ligands.

The effects of structural modifications of 2 beta-carbomethoxy-3 beta-phenyl tropane analogues were evaluated on in vitro affinity to the dopamine (DAT) and serotonin (5-HTT) transporters in rat brain tissue. The introduction of a large alkyl group at the 4'-position of the phenyl ring, affording 2 beta-carbomethoxy-3 beta-(4'-alkylphenyl) tropane, diminished the affinity for the DAT whereas moderate 5-HTT affinity was obtained. The introduction of an iodine at the 3'-position of the 4'-alkylphenyl, affording 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-alkylphenyl) tropane, and N-demethylation, affording 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-alkylphenyl) nortropane, improved affinity and specificity for the 5-HTT. It could be assumed from these results that the combination of these three modifications of tropane structure yielded highly selective compounds for the 5-HTT. Of the new compounds synthesized, the most selective cocaine derivative, 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-isopropylphenyl) nortropane (8d) labeled with iodine-123 or carbon-11, could be a potential ligand for exploration of the 5-HT transporter by SPET or PET.

Animals↗
PubMed2005

Synthesis and monoamine transporter binding properties of 3alpha-(substituted phenyl)nortropane-2beta-carboxylic acid methyl esters. Norepinephrine transporter selective compounds.

3alpha-(substituted phenyl)nortropane-2beta-carboxylic acid methyl esters (8a-h) showed high affinity for the norepinephrine transporter (NET). The most potent and selective compound was 3alpha-(3-fluoro-4-methylphenyl)nortropane-2beta-carboxylic acid methyl ester (8d), with a Ki of 0.43 nM at the NET and 21- and 55-fold selectivity relative to binding at the dopamine and serotonin transporters. The development of 8d makes available compounds selective for all three transporters from the same structural class.

Animals↗
PubMed2004

Potential of [(18)F]beta-CFT-FE (2beta-carbomethoxy-3beta-(4-fluorophenyl)-8-(2-[(18)F]fluoroethyl)nortropane) as a dopamine transporter ligand: A PET study in the conscious monkey brain.

A dopamine transporter (DAT) ligand 2beta-carbomethoxy-3beta-(4-fluoro-phenyl)-8-(2-[(18)F]fluoroethyl)nortropane ([(18)F]beta-CFT-FE) was synthesized and evaluated in comparison with [(11)C]beta-CFT in monkey brain using animal positron emission tomography (PET). [(18)F]beta-CFT-FE and [(11)C]beta-CFT were injected intravenously to conscious monkeys for a 91-min PET scan with arterial blood sampling for metabolite analysis. In the conscious state, [(18)F]beta-CFT-FE provided a peak about 20 min after the injection and declined thereafter in the striatum of monkey brain, while [(11)C]beta-CFT continuously increased with time up to 91 min after injection. Metabolite analysis revealed that [(18)F]beta-CFT-FE was more rapidly metabolized in plasma than [(11)C]beta-CFT. The striatal binding of both ligands was dose-dependently displaced by preadministration of a specific DAT inhibitor, GBR12909, at doses of 0.5 and 5 mg/kg; however, the displacement degree of [(11)C]beta-CFT-FE was higher than that of [(18)F]beta-CFT. The effects of the anesthetics, ketamine and isoflurane, on binding were more prominent in [(11)C]beta-CFT than [(18)F]beta-CFT-FE. Specificity and affinity of beta-CFT-FE to DAT were evaluated in an in vitro assay using cloned human DAT, serotonin transporter, and norepinephrine transporter in comparison with other conventional DAT ligands, showing that beta-CFT-FE had lower affinity and higher specificity to DAT than beta-CFT and beta-CIT. These results suggested that [(18)F]beta-CFT-FE could be a potential imaging agent for DAT, providing excellent selectivity and tracer kinetics for quantitative PET imaging.

Anesthetics↗
PubMed1995

Regional brain uptake and pharmacokinetics of [123I]N-omega-fluoroalkyl-2 beta-carboxy-3 beta-(4-iodophenyl)nortropane esters in baboons.

Four N-omega-fluoroalkyl-2 beta-carboxy-3 beta-(4-iodophenyl)nortropane ester (beta-CIT-FE), N-fluoropropyl, methyl ester (beta-CIT-FP), N-fluoroethyl, isopropyl ester (IP-beta-CIT-FE), and N-fluoropropyl, isopropyl ester (IP-beta-CIT-FP)] were labeled with 125I and evaluated in baboons by dynamic SPECT regional brain imaging, measurement of pharmacokinetics in arterial plasma, and whole body imaging. The labeled tracers were prepared by iododestannylation of the corresponding 4-(trimethylstannyl)phenyl compounds in radiochemical yield 63-96% and radiochemical purity > 96%. Regional SPECT brain imaging was carried out over a period of 5 h with a Strichman 810X Brain Imager to assess regional uptake in the striatum and midbrain compared to reference regions in the occipital cortex and cerebellum; arterial blood samples were taken for analysis of metabolites by solvent extraction and HPLC. The methyl esters showed higher total and specific peak uptake in the striatum than the isopropyl esters. Midbrain uptake was uniformly lower than striatal uptake and washed out more rapidly. beta-CIT-FE had more rapid striatal kinetics than beta-CIT-FP, with specific striatal washout rates of 10-14 vs 4-6% peak/h. Biodistribution of [123I] beta-CIT-FE and [123I] beta-CIT-FP measured by whole body conjugate imaging demonstrated major uptake in the brain, liver, and GI tract, with excretion occurring through both the renal and hepatobiliary routes. Absorbed radiation does estimates based on the MIRD schema indicated highest dose rates to the urinary bladder wall and lower large intestine wall (0.7 and 0.6 rad/mCi for [123I] beta-CIT-FE and 0.7 and 0.9 rad/mCi for [123I]beta-CIT-FP, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Synthesis and biological evaluation of bicyclic and tricyclic substituted nortropane derivatives: discovery of a novel selective alpha1D-adrenergic receptor ligand.

A range of 3,6,6-trisubstituted nortropane derivatives based upon 6beta-phenyltropane-3beta,6 alpha-diol have been synthesised from 6beta-hydroxytropinone, including some novel related tricyclic hemi-ketal and tricyclic ketal compounds. Derivatives were assessed for pharmacological affinity and selectivity at alpha(1)-adrenergic receptors, and 6beta-phenyl-8-azabicyclo[3.2.1]octan-3-spiro-2'-(1',3'-dioxolane)-6-ol, a novel lead compound selective for the alpha(1D)-adrenergic receptor, is reported.

Animals↗