Synthesis and in vivo studies of the stereoisomers of N-[11C]methyl-homoepibatidine

Patt, J. T.; Spang, Jörg E; Buck, Alfred; Cristina, Heidi; Arras, Margarete; Schubiger, P. August; Westera, G.

doi:10.1016/s0969-8051(01)00225-6

Cited by 18 publications

(3 citation statements)

References 40 publications

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“…The reported toxicity of N-methylepibatidine, however, is too high to ensure a safety margin for human studies [77,128]. Similar findings were reported during the evaluation of stereoisomers of [ 11 CH 3 ]N-methylhomoepibatidine in rats and pigs, where despite appropiate kinetic profiles allowing quantification, toxicity concerns preclude their use in humans [129]. Comparison of [ 11 CH 3 ]methylepibatidine with [ 11 CH 3 ]methylnorchloroepibatidine and 7-[ 11 CH 3 ]methyl-2-(pyridin-2-yl)-7-azabicyclo[2.2.1]heptane in rats using an animal PET scanner demonstrated that 7-[ 11 CH 3 ]methyl-2-(pyridin-2-yl)-7-azabicyclo[2.2.1]heptane had a lower brain uptake and lower specific binding than did [ 11 CH 3 ]methyl-norchloroepibatidine [130].…”

Section: A New Imaging Studies With Previously Developed Radiolabelesupporting

confidence: 58%

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Horti¹,

Villemagne²

2006

CPD

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Neuronal nicotinic acetylcholine receptors (nAChRs), ubiquitously distributed in the human brain, are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of Alzheimer's and Parkinson's diseases, Tourette's syndrome, epilepsy, schizophrenia, depression, and anxiety, as well as being particularly affected in tobacco dependence/withdrawal. In the past two decades, researchers have developed an extensive series of radioligands for the assessment of nAChRs in vivo through emission tomography, PET and SPECT. Several radioligands, derivatives of A-85380: 2-[(18)F]FA, 6-[(18)F]FA and 5-[(123)I]IA, are now being employed for the evaluation of nAChR in humans with PET and SPECT. Displaying better imaging properties than (11)C-nicotine and a better toxicity profile than epibatidine analogs, they have allowed quantification of thalamic nAChR in the human brain. Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio. Current research efforts on the part of PET/SPECT radiochemists, therefore, have focused on development of new, highly specific and highly selective nAChR radioligands with improved brain kinetics that are able to localize high-affinity nAChRs in vivo. Key examples of new PET/SPECT ligands that are derived from several different structural classes are discussed along with a review of their chemical as well as their in vitro and/or in vivo properties. In particular, new PET nAChR radioligands will be examined that either present faster brain kinetics allowing simple and reliable quantification approaches or higher binding potentials suitable for the evaluation of extrathalamic nAChR.

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Section: A New Imaging Studies With Previously Developed Radiolabelesupporting

confidence: 58%

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Horti¹,

Villemagne²

2006

CPD

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“…The validation of the results is often hampered by the lack of complementary in vivo imaging, and therefore the reliability of the in vitro data may be increased by choosing an animal model that is suitable for both in vitro autoradiography and neuroimaging studies. Because the suitability of pig as a laboratory animal for studying neurotransmitter systems in living brain was recently shown in PET studies of cholinergic neurotransmission (Patt et al, 1999(Patt et al, , 2001, pig was chosen in the current study to evaluate the spatial binding of the PET ligand 2-[ 18 F]F-A-85380 by quantitative in vitro autoradiography. An attempt to assess the receptor-subtype specificity of 2-[ 18 F]F-A-85380 was made by competitive autoradiography.…”

Section: Introductionmentioning

confidence: 99%

Autoradiography of 2‐[¹⁸F]F‐A‐85380 on nicotinic acetylcholine receptors in the porcine brain in vitro

Deuther‐Conrad¹,

Wevers

Becker

et al. 2005

Synapse

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Noninvasive molecular imaging of subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) will provide information on the role of these receptors in neurodegenerative diseases. The binding of the positron emission tomography ligand 2-[18F]F-A-85380 to nAChRs was investigated in the porcine brain by quantitative autoradiography in vitro. The high-affinity binding of 2-[18F]F-A-85380 to each of the investigated 12 brain areas was saturable and apparently monophasic (e.g., apparent KD value of 1.72 nM in the thalamus). The highest density of specific binding sites was observed in the thalamus (1,158 fmol/mg protein), and the lowest density was measured in the cerebellar gray matter (11 fmol/mg protein). An attempt to assess nAChR subtype specificity of 2-[18F]F-A-85380 was made by competitive autoradiography. Binding of 2-[18F]F-A-85380 coincubated with 2-F-A-85380, epibatidine, cytisine, or methyllycaconitine, respectively, indicated a specificity of 2-[18F]F-A-85380 to beta2-containing nAChRs in the porcine brain. The autoradiographic data confirmed the suitability of swine as a model for the evaluation of radioligands designed for imaging of nAChR subtypes in the living brain.

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“…Several epibatidine analogues have been synthesized and labelled with carbon-11, fluorine-18, bromine-76, and iodine-123. [8][9][10][11] More recently, a series of 3-pyridyl ether compounds that are more selective for the a4b2 subtype has been reported. One of the first derivatives, A-85380, has an affinity comparable with epibatidine and has been labelled with iodine-123 12,13 and fluorine-18.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of [¹⁸F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine ([¹⁸F]NicFP): a potential α4β2 nicotinic acetylcholine receptor radioligand for PET

Dumont

Sultana

Balter

et al. 2003

Labelled Comp Radiopharmac

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SummaryNicotinic acetylcholine receptors are widely distributed throughout the human brain and are believed to play a role in several neurological and psychiatric disorders. In order to identify an effective PET radioligand for in vivo assessment of the a4b2 subtype of nicotinic receptor, we synthesized [ purification by HPLC, the radiochemical yield was determined to be 11.3 AE 2.1% and the specific activity was 0.47 AE 0.18 Ci/mmol (EOS, n = 3). The time of synthesis and purification was 99 AE 2 min. The final product was prepared as a sterile saline solution suitable for in vivo use.

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Synthesis and in vivo studies of the stereoisomers of N-[11C]methyl-homoepibatidine

Cited by 18 publications

References 40 publications

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Autoradiography of 2‐[¹⁸F]F‐A‐85380 on nicotinic acetylcholine receptors in the porcine brain in vitro

Synthesis of [¹⁸F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine ([¹⁸F]NicFP): a potential α4β2 nicotinic acetylcholine receptor radioligand for PET

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Synthesis and in vivo studies of the stereoisomers of N-[11C]methyl-homoepibatidine

Cited by 18 publications

References 40 publications

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Autoradiography of 2‐[18F]F‐A‐85380 on nicotinic acetylcholine receptors in the porcine brain in vitro

Synthesis of [18F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine ([18F]NicFP): a potential α4β2 nicotinic acetylcholine receptor radioligand for PET

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Autoradiography of 2‐[¹⁸F]F‐A‐85380 on nicotinic acetylcholine receptors in the porcine brain in vitro

Synthesis of [¹⁸F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine ([¹⁸F]NicFP): a potential α4β2 nicotinic acetylcholine receptor radioligand for PET