Pharmacological Profile of CEB-1957 and Atropine toward Brain Muscarinic Receptors and Comparative Study of Their Efficacy against Sarin Poisoning

Trovero, Fabrice; Brochet, Denis; Breton, P.; Tambute, A.; Bégos, Arlette; Bizot, Jean-Charles

doi:10.1006/taap.1998.8423

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…Determination of nonspecific binding using 0.4 μM [ 11 C]AF150(S) was performed with 100 nM atropine. This concentration of atropine was approximately 100 times its K i value (0.82 nM) for M1ACh‐R, that is, sufficient to achieve maximal displacement of M1ACh‐R binding and low enough not to affect σ 1 binding sites ( K i value > 10 μM) . The concentration of haloperidol of 100 nM was chosen to avoid an effect on M1ACh‐R binding ( K i value of 2140 ± 572 nM), whilst having a maximal effect on σ 1 binding sites ( K i value of 0.900 ± 0.067 nM) .…”

Section: Discussionmentioning

confidence: 99%

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)

Buiter

Leysen

Schuit

et al. 2012

Labelled Comp Radiopharmac

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Purpose M1 muscarinic acetylcholine receptor (M1ACh‐R) agonists are potential therapeutics for cognitive disorders. The aim of this study was to develop an orthosteric agonist positron emission tomography (PET) ligand for the M1ACh‐R that would provide a tool to explore the active G‐protein coupled receptor. To that extend, the radiosynthesis, receptor binding in vitro, and brain uptake of [11C]AF150(S), a selective M1ACh‐R agonist, were investigated. Procedures [11C]AF150(S) was synthesized, its binding properties were investigated using autoradiography on rat brain sections, and brain uptake was determined in biodistribution studies ex vivo in rats. Metabolites in brain and blood were measured using high‐performance liquid chromatography. Results Yield of the [11C]AF150(S) radiosynthesis was 69 ± 9% with radiochemical purity >99%. The logDoct,7.4 was 0.05. Autoradiography showed binding in M1ACh‐R rich brain areas and selective inhibition by muscarinic agents in conditions promoting agonist binding. Biodistribution studies revealed rapid and high brain uptake, to levels exceeding five times the blood level. In M1ACh‐R rich areas, specific uptake versus cerebellum was apparent, remaining constant over 60 min in spite of rapid decline of radioactivity from the brain and rapid peripheral metabolism. Brain uptake of [11C]AF150(S) may involve facilitated transport. Conclusion [11C]AF150(S) was successfully synthesized, showed M1ACh‐R agonist binding properties, and high brain uptake. It provides an interesting lead for the development of an M1ACh‐R agonist PET ligand meant to explore the active receptor state. Copyright © 2012 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)

Buiter

Leysen

Schuit

et al. 2012

Labelled Comp Radiopharmac

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“…The in vivo inhibition of VC-004 binding to central muscarinic receptors by atropine (2.5 mg/kg), a muscarinic antagonist which shows nanomolar affinity toward all subtypes in in vitro binding assays (Trovero et al, 1998), was significantly less than inhibition by either scopolamine or cold VC-004. The reduction of 11 C uptake in the studied brain regions by atropine (0.5 mg/kg) was not significantly different from the inhibition of binding by (R)-(-)-QNB, with the pons as the only exception.…”

Section: Discussionmentioning

confidence: 95%

Preclinical testing of N-[11c]-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, a novel radioligand for detection of cerebral muscarinic receptors using PET

Visser

Waarde

Doze

et al. 2000

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The muscarinic antagonist N-[(11)C]methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate (VC-004) 1 was tested for visualization of muscarinic receptors in the brain. The active (R)-isomer (pKb = 10.92) was labeled by reacting [(11)C]-CH(3)I with the secondary amine precursor (40-60% decay-corrected radiochemical yield, specific activity 13.0-34.3 TBq/mmol, 45 min after end of bombardment). Biodistribution studies were performed in male Wistar rats. Brain uptake of (R)-[(11)C]-VC-004 was high, standard uptake values (SUVs) ranging from 1.6 in cerebellum to 3.3 in frontal cortex. In all brain regions, the nonsubtype selective muscarinic antagonist scopolamine (2.5 mg/kg) blocked (R)-[(11)C]-VC-004 binding to the same extent (84.6 +/- 3.3%) as nonlabeled (R)-VC-004 (2.0 mg/kg, 83.2 +/- 4.6%). In contrast, the fraction of [(11)C]VC-004 binding which was blocked by atropine (2.5 mg/kg) was significantly smaller (54 +/- 17%). The reduction of (R)-[(11)C]-VC-004 binding by low-dose atropine (0.5 mg/kg) was not significantly different from that caused by (R)-(-)-QNB (20 microg/kg). The decrease in specific binding of (R)-[(11)C]VC-004 after (R)-(-)-QNB block correlated well with literature values for the percentages of M(2) receptors in the brain regions studied. (R)-[(11)C]VC-004 was rapidly cleared from plasma (92% with a half-life of 0.27 min) and the fraction of total plasma radioactivity representing parent compound decreased from 99% to 42% at 10 min postinjection. Although (R)-[(11)C]VC-004 can visualize muscarinic receptors in the brain, it does not show selectivity for the M(2)-subtype. A low dose (0.5 mg/kg) of atropine seems to preferentially block M(2)-receptors in vivo, as has been reported for (R)-(-)-QNB.

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“…5‐HT may operate in some such indirect fashion on ACh release in the OT, through receptors that did not feature in our agonist or antagonist schedules. Clarification would require a systematic investigation with agonists and antagonists for both transmitters, including a muscarinic antagonist (or toxin) more specific than atropine, which is equipotent against the known muscarinic receptor subtypes (Trovero et al. , 1998).…”

Section: Discussionmentioning

confidence: 99%

Serotonin modulates glutamatergic transmission in the rat olfactory tubercle

Hadley

Halliwell

2010

Eur J of Neuroscience

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The olfactory tubercle (OT) is found in the brains of mammals that are highly dependent on their sense of smell. Its human analogue is the poorly understood anterior perforated substance. Previous work on rat brain slices identified two types of field potential responses from the OT. The association fibre (AF) pathway was sensitive to muscarinic modulation, whereas the lateral olfactory tract (LOT) fibre pathway was not. Here, we establish that serotonin (5-hydroxytryptamine; 5-HT) also inhibits field potential excitatory postsynaptic potentials (EPSPs) in the AF, but not in the LOT fibre, pathway. Parallel experiments with adenosine (ADO) excluded ADO mediation of the 5-HT effect. Exogenous 5-HT at 30 microm caused a long-lasting approximately 40% reduction in the amplitude of AF postsynaptic responses, without affecting the time-course of EPSP decline, indicating a fairly restricted disposition of the 5-HT receptors responsible. The 5-HT(1)-preferring, 5-HT(5)-preferring and 5-HT(7)-preferring agonist 5-carboxamidotryptamine caused similar inhibition at approximately 100 nm. The 5-HT(1A)-preferring ligand 8-hydroxy-di-n-propylamino-tetralin at 10 microm, and the 5-HT uptake inhibitor citalopram at 3 microm, caused inhibition of AF-stimulated field potential responses in the 5-10% range. Order-of-potency information suggested a receptor of the 5-HT(1B) or 5-HT(1D) subtype. The 5-HT(1D) agonist L-694,247 (1 microm) suppressed the AF response by approximately 10% when used on its own. After washing out of L-694,427, inhibition by 30 microm 5-HT was reduced to negligible levels. Allowing for a partial agonist action of L-694,427 and complex interactions of 5-HT receptors within the OT, these results support the presence of active 5-HT(1D)-type receptors in the principal cell layer of the OT.

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Pharmacological Profile of CEB-1957 and Atropine toward Brain Muscarinic Receptors and Comparative Study of Their Efficacy against Sarin Poisoning

Cited by 7 publications

References 27 publications

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)

Preclinical testing of N-[11c]-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, a novel radioligand for detection of cerebral muscarinic receptors using PET

Serotonin modulates glutamatergic transmission in the rat olfactory tubercle

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Pharmacological Profile of CEB-1957 and Atropine toward Brain Muscarinic Receptors and Comparative Study of Their Efficacy against Sarin Poisoning

Cited by 7 publications

References 27 publications

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [11C]AF150(S)

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [11C]AF150(S)

Preclinical testing of N-[11c]-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, a novel radioligand for detection of cerebral muscarinic receptors using PET

Serotonin modulates glutamatergic transmission in the rat olfactory tubercle

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Product

Resources

About

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)