Comparison of N-[11C]methyl-norchloroepibatidine and N-[11C]methyl-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane with N-[11C]methyl-epibatidine in small animal PET studies

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

doi:10.1016/s0969-8051(00)00080-9

Cited by 12 publications

(6 citation statements)

References 36 publications

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“…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]. The latter radioligand presented the best overall characteristics for nAChR binding: high brain uptake, high levels of specific binding and faster kinetics.…”

Section: A New Imaging Studies With Previously Developed Radiolabelementioning

confidence: 99%

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 Radiolabelementioning

confidence: 99%

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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“…All enantiomers were separated on a chiral ChirobioticT column in analogy to the procedures described recently [24,34,63]. Optical purity of enantiomers was checked with the same HPLC set-up as used for the semipreparative separations.…”

Section: Separation Of the Enantiomersmentioning

confidence: 99%

Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors

Spang

Bertrand²,

Westera

et al. 2000

Chemistry & Biology

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“…The density value ( B max ) of the α4β2-nAChR is highest in the thalamus (10−60 fmol/mg protein) and lower in the extrathalamic regions such as the cortex (4−21 fmol/mg protein). − Most cerebral receptors that have been successfully studied by PET (for example, D 1 , D 2 , μ-opiate, and benzodiazepine receptors) display substantially higher densities − than those of the α4β2-nAChR. Because of low density of α4β2-nAChR, radioligands with very high binding affinities have been synthesized for PET imaging. − For imaging extrathalamic α4β2-nAChRs, radioligands with even higher binding affinity are necessary.…”

Section: Introductionmentioning

confidence: 99%

5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography

et al. 2004

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Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from -1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at alpha4beta2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[(18)F]fluoro-5-(pyridin-3-yl)-A-85380 ([(18)F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[(18)F]fluoropyridin-5-yl)pyridine) ([(18)F]35), were radiolabeled with (18)F. Comparison of PET data for [(18)F]31 and 2-[(18)F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [(18)F]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[(18)F]FA. Therefore, [(18)F]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.

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Comparison of N-[11C]methyl-norchloroepibatidine and N-[11C]methyl-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane with N-[11C]methyl-epibatidine in small animal PET studies

Cited by 12 publications

References 36 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

Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors

5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography

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