Pyridazines and their Benzo Derivatives

Maes, Bert U. W.; Lemière, Guy L. F.

doi:10.1016/b978-008044992-0.00701-x

Cited by 7 publications

(5 citation statements)

References 551 publications

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“…Despite these advances, multiple-step synthesis or harsh conditions, such as high temperature and microwave, are required to achieve satisfactory efficiency. Based on these previous reports, we hypothesized that 3-(tributylstannyl)pyridin-4-amine 2 would be a good precursor for our desired target compound [ 11 C]3Me4AP 3 , considering the stability and functional group tolerance of tributylstannyl precursors in cross-coupling reactions . Consequently, 2 was prepared from 3-iodopyridin-4-amine 1 without preprotection in one pot via sequential deprotonation, lithium–halogen exchange, and stannylation in a 49% isolated yield (Figure A, equation 1).…”

Section: Resultsmentioning

confidence: 99%

“…Based on these previous reports, we hypothesized that 3-(tributylstannyl)pyridin-4-amine 2 would be a good precursor for our desired target compound [ 11 C]3Me4AP 3, considering the stability and functional group tolerance of tributylstannyl precursors in cross-coupling reactions. 30 Consequently, 2 was prepared from 3-iodopyridin-4-amine 1 without preprotection in one pot via sequential deprotonation, lithium−halogen exchange, and stannylation in a 49% isolated yield (Figure 1A 1B). The product was purified using normal-phase semipreparative HPLC.…”

Section: ■ Introductionmentioning

confidence: 99%

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Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Sun

Guehl

Zhou

et al. 2022

ACS Chem. Neurosci.

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Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium channels Kv1.1 and Kv1.2, generally under the myelin sheath, become exposed and upregulated. Therefore, imaging these channels using positron emission tomography can provide valuable information for disease diagnosis and monitoring. Here, we describe a novel tracer for Kv1 channels, [11C]3-methyl-4-aminopyridine ([11C]3Me4AP). [11C]3Me4AP was efficiently synthesized via Pd(0)–Cu(I) comediated Stille cross-coupling of a stannyl precursor containing a free amino group. Evaluation of its imaging properties in rats and nonhuman primates showed that [11C]3Me4AP has a moderate brain permeability and slow kinetics. Additional evaluation in monkeys showed that the tracer is metabolically stable and that a one-tissue compartment model can accurately model the regional brain time–activity curves. Compared to the related tracers [18F]3-fluoro-4-aminopyridine ([18F]3F4AP) and [11C]3-methoxy-4-aminopyridine ([11C]3MeO4AP), [11C]3Me4AP shows lower initial brain uptake, which indicates reduced permeability to the blood–brain barrier and slower kinetics, suggesting higher binding affinity consistent with in vitro studies. While the slow kinetics and strong binding affinity resulted in a tracer with less favorable properties for imaging the brain than its predecessors, these properties may make 3Me4AP useful as a therapeutic.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Sun

Guehl

Zhou

et al. 2022

ACS Chem. Neurosci.

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show abstract

“…Despite these advances, multiple-step synthesis 23 or harsh conditions (18) , such as high temperature and microwave, are required to achieve satisfying efficiency. Based on these previous reports, we hypothesized that 3-(tributylstannyl)pyridin-4-amine 2 would be a good precursor for our desired target compound [ 11 C]3Me4AP 3 , considering the stability and functional group tolerance of tributylstannyl precursors in cross-coupling reactions 24 . Consequently, 2 was prepared from 3-iodopyridin-4-amine 1 without pre-protection in one pot via sequential deprotonation, lithium-halogen exchange and stannylation in a 49% isolated yield ( Figure 1A, Equation 1 ).…”

Section: Resultsmentioning

confidence: 99%

Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Non-Human Primates for Imaging Potassium Channels in the CNS

Sun

Guehl

Zhou

et al. 2022

Preprint

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Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium channels Kv1.1 and Kv1.2, generally under the myelin sheath, become exposed and upregulated. Therefore, imaging these channels using positron emission tomography can provide valuable information for disease diagnosis and monitoring. Here, we describe the novel tracer for Kv1 channels [11C]3-methyl-4-aminopyridine ([11C]3Me4AP). [11C]3Me4AP was efficiently synthesized via Pd(0)-Cu(I) co-mediated Stille cross-coupling of a stannyl precursor containing a free amino group. Evaluation of its imaging properties in rats and nonhuman primates showed that [11C]3Me4AP has a moderate brain permeability and slow kinetics. Additional evaluation in monkeys showed that the tracer is metabolically stable and that a 1-tissue compartment model can accurately model the regional brain time-activity curves. Compared to the related tracers [18F]3-fluoro-4-aminopyridine ([18F]3F4AP) and [11C]3-methoxy-4-aminopyridine ([11C]3MeO4AP), [11C]3Me4AP shows lower initial brain uptake, which indicates reduced permeability to the blood-brain-barrier and slower kinetics, suggesting higher binding affinity consistent within vitrostudies. While the slow kinetics and strong binding affinity resulted in a tracer with less favorable properties for imaging the brain than its predecessors, these properties may make 3Me4AP useful as a therapeutic.

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“…Aromatic pyridazine derivatives can participate as 4π-electron components in concerted cycloadditions [ 1 , 2 , 3 ]. In particular, N -oxides, N -imides, and N -ylides behave as 1,3-dipoles with different dipolarophiles and, starting from the pioneering works of Neunhoeffer [ 8 , 9 , 10 ] and Jojima [ 11 ], suitably substituted pyridazines have been exploited as azadienes in inverse electron-demand HDA reactions with electron-rich or strained dienophiles or in intramolecular processes [ 12 , 13 , 14 , 15 , 16 , 17 ].…”

Section: Hetero Diels-alder (Hda) Reactionsmentioning

confidence: 99%

“…Pyridazine and its benzo derivatives have been known since the nineteenth century, but interest in these compounds was quite limited compared to other nitrogen heterocycles, like for instance the pyrimidines, because only a few examples of naturally occurring 1,2-diazines have been reported. Anyway, in the last decades, the biological activity exhibited by many synthetic derivatives has stimulated intensive research on this heterocyclic system [ 1 , 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Reactivity and Synthetic Applications of 4,5-Dicyanopyridazine: An Overview

2010

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Despite the poor reputation of electron-deficient pyridazines in intermolecular Hetero Diels-Alder (HDA) reactions, 4,5-dicyanopyridazine (DCP) showed a surprising reactivity as a heterocyclic azadiene in inverse electron-demand HDA processes with different dienophiles. The use of alkenes, alkynes and enamines as 2π electron counterparts afforded dicyanocyclohexa-1,3-dienes and substituted phthalonitriles, respectively, while the use of suitable bis-dienophiles provides a general strategy for the one-pot synthesis of polycyclic carbo- and hetero-cage systems through pericyclic three-step homodomino processes. HDA reactions with heterocyclic dienophiles allowed direct benzoannelation: in particular, pyrrole and indole derivatives were converted to dicyano-indoles and -carbazoles. In addition an unprecedented reactivity of DCP as a very reactive heterocyclic electrophile at the C-4 carbon was also evidenced: by changing the experimental conditions, cyanopyrrolyl- and cyanoindolyl-pyridazines were obtained through reactions of pyrrole and indole systems as carbon nucleophiles in formal SNAr2 processes where a CN group of DCP acts as leaving group. Thus, careful control of the reaction conditions allows exploitation of both pathways for the synthesis of different classes of heterocyclic derivatives.

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Pyridazines and their Benzo Derivatives

Cited by 7 publications

References 551 publications

Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Non-Human Primates for Imaging Potassium Channels in the CNS

Reactivity and Synthetic Applications of 4,5-Dicyanopyridazine: An Overview

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Pyridazines and their Benzo Derivatives

Cited by 7 publications

References 551 publications

Radiochemical Synthesis and Evaluation of 3-[11C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Radiochemical Synthesis and Evaluation of 3-[11C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Radiochemical Synthesis and Evaluation of 3-[11C]Methyl-4-aminopyridine in Rodents and Non-Human Primates for Imaging Potassium Channels in the CNS

Reactivity and Synthetic Applications of 4,5-Dicyanopyridazine: An Overview

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Product

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Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

Radiochemical Synthesis and Evaluation of 3-[¹¹C]Methyl-4-aminopyridine in Rodents and Non-Human Primates for Imaging Potassium Channels in the CNS