[C-11]N-methylhomoepibatidine: radiolabelling and biodistribution studies in mice

Patt, J. T.; Spang, Jörg E; Westera, G.; Schubiger, P. August

doi:10.1002/(sici)1099-1344(200002)43:2<127::aid-jlcr299>3.0.co;2-u

Cited by 8 publications

(5 citation statements)

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“…At that time, the epibatidine molecule seemed to be a very promising structure to be labeled with 11 C, 18 [43,44], was developed by two groups at the same time using different precursors for the radiochemical synthesis. Horti et al [29,41] [46], were labeled with carbon-11 or fluorine-18 as radiotracers for PET. N-[ 11 C]methyl derivatives of three halogen-substituted epibatidine analogs possess high affinity for central nicotinic acetylcholine receptors (K i = 27-36 pM) in vitro.…”

Section: In Vivo Imaging Using Epibatidine As a Prototypecontrasting

confidence: 56%

“…Since the discovery of epibatidine [28], an alkaloid extracted from the skin of the Ecuadorian poisonous frog Epipedobatus tricolor, several groups synthesized new epibatidine analogs as radiotracers for imaging nicotinic acetylcholine receptors in the brain [29][30][31][41][42][43][44][45][46][47]. [ 3 H]Epibatidine binds with an extremely high affinity to α4β2 nAChR in the rat brain [49,50] [27] showed the most promising in vitro properties for in vivo imaging uptake into the brain of mice (11.5% ID/g), a regional distribution consistent with that of nAChRs, and a slower clearance from brain than nicotine based radiotracers.…”

Section: In Vivo Imaging Using Epibatidine As a Prototypementioning

confidence: 99%

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Nicotinic Acetylcholine Receptors and Imaging

Gündisch¹

2000

CPD

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In vivo imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) offer the possibility to monitor human central nicotinic acetylcholine receptors (nAChRs) in a variety of central nervous system disorders. In the past, the only available PET radiotracer for imaging nAChRs in the human brain, [11C]-(-)-nicotine, suffered from a spectrum of not suitable properties for in vivo imaging. Current efforts are focused on the development of new, highly specific and highly selective radioligands based on different structural classes (e.g. nicotine, epibatidine, 3-pyridyl ether analogues) for central nAChRs. The most promising compounds are halogenated 3-pyridyl ether compounds for imaging alpha 4 beta 2 nAChRs. But there is still a lack for radiotracers for other subtypes of nicotinic acetylcholine receptors being a promising area of interest.

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Section: In Vivo Imaging Using Epibatidine As a Prototypecontrasting

confidence: 56%

Section: In Vivo Imaging Using Epibatidine As a Prototypementioning

confidence: 99%

Nicotinic Acetylcholine Receptors and Imaging

Gündisch¹

2000

CPD

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“…[3H]Epibatidine has been shown to bind with very high affinity to nAChR binding sites in vitro (McKay et al, 1994;Houghtling et a!., 1995;Gerzanich et al, 1995;Thang et al, 1998). In very recent studies, some analogues of epibatidine were synthesized, labeled with different radioisotopes (''C, 123j, 251, or 76Br), and tested both in vitro and in vivo to develop new, more suitable nAChR ligands for PET (Davila-Garcia et al, 1997;Loch et a!., 1997;Musachio et al, 1997;Patt et a!., 1997). The potent nicotinic ligand cytisine has been reported to displace (-) -[3H]nicotine and [3H]ABT-418 with similar potency as in this study using (S)-II"Clnicotine and ["C]ABT-418 (Marks et al, 1986;Reavill et al, 1988; Autoradiograms were obtained after incubation of frozen rat brain sections with 10 nM (S)-["C]nicotine, 10 nM ["C]MPA, and 30 nM ["C]ABT-418 for 30 mm.…”

Section: Timementioning

confidence: 99%

In Vitro Evaluation of ¹¹C‐Labeled (S)‐Nicotine, (S)‐3‐Methyl‐5‐(1‐Methyl‐2‐Pyrrolidinyl)isoxazole, and (R,S)‐1‐Methyl‐2‐(3‐Pyridyl)azetidine as Nicotinic Receptor Ligands for Positron Emission Tomography Studies

Sihver

Fasth²,

Ögren³

et al. 1998

Journal of Neurochemistry

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The binding characteristics of the novel 1~Clabeled nicotinic ligands (R , S) -1 -methyl-2-(3-pyridyl) azetidine (MPA) and (S) -3-methyl-5-(1 -methyl-2-pyrrolidinyl)isoxazole (ABT-418) were investigated in comparison with those of (S)-[11C]nicotine in vitro in the rat brain to be able to predict the binding properties of the new ligands for positron emission tomography studies in vivo. The data from time-resolved experiments for all ligands indicated fast binding kinetics, with the exception of a slower dissociation of [11C]MPAin comparison with (S)~[UC]nicotineand [UC]ABT~418. Saturation experiments revealed for all ligands two nicotinic receptor binding sites with affinity constants (Kṽ alues) of 2.4 and 560 nM and binding site densities (Bmax values) of 65.5 and 223 fmol/mg of protein for (S)-[~C]nicotine,KD values of 0.011 and 2.2 nM and Bmax values of 4.4 and 70.7 fmol/mg of protein for [~C]MPA, and K 0 values of 1.3 and 33.4 nM and Bmax values of 8.8 and 69.2 fmol/mg of protein for [ 110]ABT-418.In competing with the 11C-ligands, epibatidine was most potent, followed by cytisine. A different rank order of potencies was found for (-)--nicotine, (+)-nicotine, MPA, and ABT-418 displacing each of the~C-ligands. Autoradiograms displayed a similar pattern of receptor binding for all ligands, whereby [11C]MPAshowed the most distinct binding pattern and the lowest nonspecific binding. We conclude that the three~C-Iabelednicotinic ligands were suitable for characterizing nicotinic receptors in vitro. The very high affinity of [~C]MPA to nicotinic acetylcholine receptors, its low nonspecific binding, and especially the slower dissociation kinetics of the [~C]MPA from the putative high-affinity nicotinic acetylcholine receptor binding site compared with (S)-[°C]nicotineand [~C}ABT-418 raise the level of interest in [11C]MPA for application in positron emission tomography. Key Words: Nicotinic receptor-Positron emission tomography-(R, S) -1- [110] Methyl-2-(3-pyridyl)azetidine -(S) -3 -Methyl -5 -(1 -[UC]methyl-2 -pyrrolidinyl) isoxazole-(S) [llc] Nicotine-In vitro receptor binding.

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“…Initial studies performed with radioactive nicotine have revealed the inadequacy of this compound in PET studies and that more specific ligands must be identified to obtain proper spatial and temporal resolutions [11,12]. The identification of a new frog toxin, epibatidine, which displays a very high affinity for the neuronal nAChRs, opened new possibilities to design synthetic compounds of potential interest for PET monitoring [13–17]. We produced N ‐methylated epibatidine for this purpose [13].…”

Section: Introductionmentioning

confidence: 99%

“…The identification of a new frog toxin, epibatidine, which displays a very high affinity for the neuronal nAChRs, opened new possibilities to design synthetic compounds of potential interest for PET monitoring [13–17]. We produced N ‐methylated epibatidine for this purpose [13]. Recently this and other methylated epibatidine analogs were synthesized, with very similar biological properties (e.g.…”

Section: Introductionmentioning

confidence: 99%

Neuronal nAChR stereoselectivity to non‐natural epibatidine derivatives

Bertrand¹,

Patt

Spang

et al. 1999

FEBS Letters

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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.z 1999 Federation of European Biochemical Societies.

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[C-11]N-methylhomoepibatidine: radiolabelling and biodistribution studies in mice

Cited by 8 publications

References 0 publications

Nicotinic Acetylcholine Receptors and Imaging

Nicotinic Acetylcholine Receptors and Imaging

In Vitro Evaluation of ¹¹C‐Labeled (S)‐Nicotine, (S)‐3‐Methyl‐5‐(1‐Methyl‐2‐Pyrrolidinyl)isoxazole, and (R,S)‐1‐Methyl‐2‐(3‐Pyridyl)azetidine as Nicotinic Receptor Ligands for Positron Emission Tomography Studies

Neuronal nAChR stereoselectivity to non‐natural epibatidine derivatives

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[C-11]N-methylhomoepibatidine: radiolabelling and biodistribution studies in mice

Cited by 8 publications

References 0 publications

Nicotinic Acetylcholine Receptors and Imaging

Nicotinic Acetylcholine Receptors and Imaging

In Vitro Evaluation of 11C‐Labeled (S)‐Nicotine, (S)‐3‐Methyl‐5‐(1‐Methyl‐2‐Pyrrolidinyl)isoxazole, and (R,S)‐1‐Methyl‐2‐(3‐Pyridyl)azetidine as Nicotinic Receptor Ligands for Positron Emission Tomography Studies

Neuronal nAChR stereoselectivity to non‐natural epibatidine derivatives

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Product

Resources

About

In Vitro Evaluation of ¹¹C‐Labeled (S)‐Nicotine, (S)‐3‐Methyl‐5‐(1‐Methyl‐2‐Pyrrolidinyl)isoxazole, and (R,S)‐1‐Methyl‐2‐(3‐Pyridyl)azetidine as Nicotinic Receptor Ligands for Positron Emission Tomography Studies