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1.
Appl Radiat Isot ; 66(2): 152-7, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17919916

ABSTRACT

An approach to synthesize the electrophilic fluorinating agent no-carrier-added (n.c.a.) [18F]perchloryl fluoride ([18F]FClO3) in superacidic media in the presence of KClO4 or anhydrous perchloric acid starting from [18F]fluoride was demonstrated in this study. However, the radiochemical yields were low (1-6%) and poorly reproducible. Fluorosulphonic acid proved to be an essential intermediate as revealed by non-radioactive experiments. A key problem in the preparation of [18F]FClO3 is the assumed kinetic inhibition due to the unfavourable stoichiometric ratio of the ClO4 moiety to [18F]HSO3F.


Subject(s)
Fluorine Radioisotopes/chemistry , Perchlorates/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Electrochemistry , Humans , Perchlorates/chemistry , Positron-Emission Tomography , Radiochemistry , Radiopharmaceuticals/chemistry
2.
Eur Neuropsychopharmacol ; 18(3): 222-9, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17728108

ABSTRACT

Cholinergic neurotransmission depends on the integrity of nicotinic acetylcholine receptors (nAChRs), and impairment of both is characteristic for various neurodegenerative diseases. Visualization of specific receptor subtypes by positron emission tomography (PET) has potential to assist with diagnosis of such neurodegenerative diseases and with design of suitable therapeutic approaches. The goal of our study was to evaluate in vivo the potential of (18)F-labelled (+)- and (-)-norchloro-fluoro-homoepibatidine ([(18)F]NCFHEB) in comparison to 2-[(18)F]F-A-85380 as PET tracers. In the brains of NMRI mice, highest levels of radioactivity were detected at 20 min post-injection of (+)-[(18)F]NCFHEB, (-)-[(18)F]NCFHEB, and 2-F-[(18)F]-A-85380 (7.45, 5.60, and 3.2% ID/g tissue, respectively). No marked pharmacological adverse effects were observed at 25 mug NCFHEB/kg. Uptake studies in RBE4 cells and in situ perfusion studies suggest an interaction of epibatidine and NCFHEB with the carrier-mediated choline transport at the blood-brain barrier. The data indicate that (+)- and (-)-[(18)F]NCFHEB have potential for further development as PET tracers.


Subject(s)
Benzamides , Bridged Bicyclo Compounds, Heterocyclic , Radiopharmaceuticals , Receptors, Nicotinic/metabolism , Animals , Azetidines , Benzamides/chemistry , Benzamides/pharmacokinetics , Biological Transport, Active , Blood-Brain Barrier/drug effects , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Choline/metabolism , Female , Indicators and Reagents , Isotope Labeling , Male , Mice , Perfusion , Positron-Emission Tomography , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Stereoisomerism , Tissue Distribution
3.
Nucl Med Biol ; 28(6): 645-55, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11518646

ABSTRACT

The carbon-11 labeled enantiomers of nicotinic acetylcholine receptor (nAChR) ligand N-[11C]methyl-homoepibatidine have been synthesized to study the neuronal nicotinic acetylcholine receptors (nAChRs). In vivo evaluations were performed in mice and pig using positron emission tomography (PET). The radioligands displayed a strong enantioselectivity. The (-)-enantiomer showed high uptake in the brain while the (+)-enantiomer was rapidly washed out. In metabolite studies in mice >65% unchanged ligand was found in the blood after 60 minutes. No metabolites were found in the brain. After intravenous application of N-[11C]methyl-(-)-homoepibatidine in the pig specific accumulation in the thalamus was seen. Blocking experiments with cytisine showed specific binding consistent with labeling of the alpha4beta2-nAChR-subtype in the brain. Quantitative kinetic modeling of radiotracers in the pig brain was performed using the arterial input function. The brain uptake of the (-)-isomer was best fitted by a three-compartment model. High distribution volumes were found in the thalamus (DV(TOT) = 66.617, DV(S) = 59.910) versus a low uptake in the cerebellum (DV(TOT) = 8.605m, DV(S) = 1.898). The binding characteristics suggest N-[11C]methyl-(-)-homoepibatidine to be suited for PET imaging studies, but high toxicity prevents routine use in humans.


Subject(s)
Brain/diagnostic imaging , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Nicotinic Agonists/metabolism , Pyridines/metabolism , Animals , Brain/drug effects , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/toxicity , Female , Lethal Dose 50 , Male , Mice , Mice, Inbred ICR , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/chemistry , Nicotinic Agonists/toxicity , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/toxicity , Rats , Species Specificity , Stereoisomerism , Swine , Tomography, Emission-Computed
4.
Nucl Med Biol ; 28(4): 383-9, 2001 May.
Article in English | MEDLINE | ID: mdl-11395310

ABSTRACT

[(123)I]AIBZM, (S)-5-[(123)I]-Iodo-N-[(1-ethyl-2-pyrrolidinyl)]methyl-4-amine-2-methoxybenzamide is a derivative with high affinity for the D2 receptor. Labeling was achieved by the Iodogen method. The in vivo affinity for the D2 receptor and the biological characteristics were performed in rats. The brain uptake of [(123)I]AIBZM was significantly lower, however the striatum/cerebellum ratio (2h p.i.) was higher than that of [(123)I]IBZM. Because of the high affinity and its possibly lower unspecific binding compared to [(123)I]IBZM, [(123)I]AIBZM may be a potential imaging agent for the D2 dopamine receptor.


Subject(s)
Benzamides/pharmacokinetics , Brain/diagnostic imaging , Pyrrolidines/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Receptors, Dopamine D2/metabolism , Animals , Autoradiography , Blood Proteins/metabolism , Brain Chemistry , Chemical Phenomena , Chemistry, Physical , Protein Binding , Radionuclide Imaging , Rats , Rats, Sprague-Dawley , Tissue Distribution
5.
Chem Biol ; 7(7): 545-55, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10903939

ABSTRACT

BACKGROUND: Studies of ligand gated channels strongly rely on the availability of compounds that can activate or inhibit with high selectivity one set or a subset of defined receptors. The alkaloid epibatidine (EPB), originally isolated from the skin of an Ecuadorian poison frog, is a very specific agonist for the neuronal nicotinic acetylcholine receptors (nAChRs). We used EPB derivatives to investigate the pharmacophore of nAChR subtypes. RESULTS: Optically pure enantiomers of EPB analogues were synthesised. Analogues were obtained altered in the aromatic part: the chlorine was eliminated and the relative position of the pyridyl nitrogen changed. Voltage clamp electrophysiology was performed with these compounds on neuronal nAChRs reconstituted in Xenopus oocytes. The EPB derivatives show different activities towards the various nAChR subtypes. CONCLUSIONS: Small changes in the molecular structure of EPB produce marked changes in its capacity to activate the nAChRs. Subtype specificity can be obtained by changing the position of or by eliminating the pyridyl nitrogen.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Nicotinic Antagonists/chemistry , Protein Isoforms/drug effects , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Amino Acid Motifs , Animals , Binding Sites , Dose-Response Relationship, Drug , Microinjections , Models, Chemical , Molecular Structure , Neurons/metabolism , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Patch-Clamp Techniques , Protein Isoforms/metabolism , Rats , Receptors, Nicotinic/chemistry , Recombinant Fusion Proteins , Sequence Alignment , Stereoisomerism , Structure-Activity Relationship , Xenopus
6.
Nucl Med Biol ; 27(3): 239-47, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10832080

ABSTRACT

Structural variations of the nicotinic acetylcholine receptor radioligand N-[(11)C]methyl-epibatidine were made to form (11)C-labeled N-methyl-norchloroepibatidine (N-methyl-NorchloroEPB) and N-methyl-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (N-methyl-2PABH). Radiosyntheses were performed by methylation with high radiochemical purities (>98%) and with specific activities between 140 and 500 GBq/micromol at the end of synthesis. The radiochemical yield (decay-corrected, related to [(11)C]CH(3)I) was between 5 and 10%. Positively and negatively radiolabeled enantiomers were prepared in high optical purity (>98%ee) by labeling of the appropriate optically active substrates, which were obtained via chiral high performance liquid chromatography. For in vivo studies radioligands were administered intravenously in rats. Brain uptake curves were acquired and combined with blocking experiments. Brain uptake of N-[(11)C]methyl-NorchloroEPB was similar to that of N-[(11)C]methyl-EPB whereas N-[(11)C]methyl-2PABH with the modified pyridine ring had a significantly lower uptake.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Pyridines , Radiopharmaceuticals , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Cytosine/metabolism , Injections, Intravenous , Lipids/chemistry , Male , Pyridines/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Rats , Rats, Sprague-Dawley , Spectrophotometry, Ultraviolet , Stereoisomerism , Tissue Distribution , Tomography, Emission-Computed , Whole-Body Counting
7.
Eur J Pharmacol ; 393(1-3): 155-63, 2000 Mar 30.
Article in English | MEDLINE | ID: mdl-10771009

ABSTRACT

Interest in the field of nicotinic receptors has been recently stimulated both by the discovery of the potential therapeutic effects of new agonists, and by the discovery of an association between nicotinic receptor mutations and human neurological diseases. Expression of human receptors in an exogenous system allows their study in isolation. Receptors reconstituted by pairwise injection of either alpha4 or alpha3 with beta2 or beta4 subunits displayed important differences between the resulting receptor subtypes. These results were further compared with those obtained with alpha3:alpha4 fusion proteins. The modifications of either the ligand-binding site in the N-terminal domain or in the ionic pore domain were found to affect the pharmacological properties of the receptors. Finally, the analysis of non-natural derivatives of epibatidine demonstrates how an agonist can be modified to be selective at one receptor subtype or to become an antagonist. These data are well explained on the basis of a three-state allosteric model.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Receptors, Nicotinic/physiology , Acetylcholine/pharmacology , Allosteric Regulation , Amino Acid Sequence , Animals , Binding, Competitive , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Electrophysiology , Humans , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Membrane Proteins/physiology , Molecular Sequence Data , Neurons , Nicotinic Agonists/chemistry , Polymerase Chain Reaction , Pyridines/chemistry , Rats , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/metabolism , Recombinant Fusion Proteins/metabolism , Sequence Homology, Amino Acid , Transfection , Xenopus
8.
FEBS Lett ; 450(3): 273-9, 1999 May 07.
Article in English | MEDLINE | ID: mdl-10359088

ABSTRACT

The frog toxin epibatidine is one of the most powerful ligands of the neuronal nicotinic receptors and derivatives show promising possibilities for labeling in positron emission tomography studies. In an attempt to reduce epibatidine toxicity, new methyl derivatives were synthesized, tested in positron emission tomography imaging and in electrophysiology. labeling as well as physiological experiments highlighted the differences in sensitivity of the neuronal nicotinic acetylcholine receptors between two methyl enantiomers and the reduction in sensitivity caused by introducing the methyl group. At present, epibatidine derivatives seem the most promising compounds for in vivo labeling of neuronal nicotinic acetylcholine receptors.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/metabolism , Neurons/metabolism , Nicotinic Agonists/metabolism , Pyridines/metabolism , Receptors, Nicotinic/metabolism , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Ganglia/metabolism , Male , Nicotinic Agonists/chemistry , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Tomography, Emission-Computed , Xenopus
9.
Nucl Med Biol ; 26(2): 165-73, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10100215

ABSTRACT

The carbon-11-labelled nicotinic acetylcholine receptor (nAChR) agonist N-methylepibatidine was evaluated in vitro and in vivo as a possible positron emission tomography (PET)-tracer for nicotinic receptors in the central nervous system (CNS). The racemic mixture and both enantiomers of N-methylepibatidine were compared. Biodistribution and metabolites for blood and brain of [C-11]N-methylepibatidine were determined in mice. Whole body rat PET data were acquired for both stereoisomers. The regional distribution of the N-methyl-(-)-epibatidine in the brain was determined by a PET scan in a pig. Characteristic differences were found for the in vivo behavior of the stereoisomers of [C-11]N-methylepibatidine.


Subject(s)
Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Nicotinic Agonists/metabolism , Pyridines/metabolism , Tomography, Emission-Computed , Animals , Bridged Bicyclo Compounds, Heterocyclic/blood , Bridged Bicyclo Compounds, Heterocyclic/toxicity , Carbon Radioisotopes , Chromatography, High Pressure Liquid , Female , Male , Mice , Mice, Inbred ICR , Nicotinic Agonists/blood , Nicotinic Agonists/toxicity , Pyridines/blood , Pyridines/toxicity , Rats , Stereoisomerism , Tissue Distribution , Toxicity Tests
10.
J Recept Signal Transduct Res ; 19(1-4): 521-31, 1999.
Article in English | MEDLINE | ID: mdl-10071782

ABSTRACT

The new epibatidine analogue exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (2PABH) was synthesised. Separation of enantiomers was performed on chiral HPLC chromatography in polar-organic phase mode at 0 degree C. Enantiomeric purity was greater than 99.8%ee for the (-)- and 90.5%ee for the (+)-enantiomer respectively. Optical rotation was determined to be [alpha]23D = +/- 13 degrees. Electrophysiological studies of 2PABH were carried out on alpha 4 beta 2, alpha 3 beta 4 and alpha 7 nAChR subtypes cloned from rat and reconstituted in Xenopus oocytes. Both enantiomers could not significantly activate the heteromeric subtypes. The homomeric alpha 7 nAChR displays a high sensitivity only towards (-)-2PABH. The EC50 for (-)-2PABH and ACh were determined (32.5 +/- 9.5 microM, 137.3 +/- 16.5 microM). (-)-2PABH was shown to be a partial agonist (80% of ACh). Thus the efficacy of 2PABH differs markedly from that of epibatidine. The intramolecular N-N-distance and the spatial pyridine nitrogen orientation play a central role in nAChR recognition.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Nicotinic Agonists/chemical synthesis , Pyridines/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Electrophysiology , Female , In Vitro Techniques , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Oocytes/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptors, Nicotinic/classification , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/metabolism , Recombinant Proteins/classification , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Stereoisomerism , Structure-Activity Relationship , Xenopus laevis
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