Synthesis of carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potential PET AMPA receptor ligands

Gao, Mingzhang; Kong, Deyuan; Clearfield, Abraham; Zheng, Qi‐Huang

doi:10.1016/j.bmcl.2006.01.042

Cited by 53 publications

(21 citation statements)

References 7 publications

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“…As depicted in Chart 1 a small series of 2-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives (6a-f) was prepared following previously reported procedures 17,23) with slight modifications. In particular, we employed an efficient high-speed microwave-assisted synthetic approach (Chart 1) optimizing the chemical yield and purity as well as greatly reducing the reaction times and solvent Europa-Germaneto, 88100 Catanzaro, Italy.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure-Active Relationship of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Anticonvulsants

Gitto

Luca

Ferro

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Epilepsy is commonly considered the result of an imbalance between excitatory and inhibitory "tone" leading to periodic and unpredictable seizures related to an abnormal discharge of cerebral neurons. Epilepsy is one of the most common neurological disorders, affecting ca. 1% of the population worldwide, and the incidence increases to 3% by the age of 75 years. Although most people become seizure-free with drug therapy, there is still a significant number of patients (30%) who are resistant to the currently available antiepileptic drugs whether used alone or in combination. The pathophysiology of epilepsy is complex and several mechanisms play a role in epileptogenesis and epileptogenicity.1) The efficacy of anticonvulsant drugs may be connected with different molecular targets to reduce the excitability of neurons involved in seizure onset.2) The mechanism of action of currently available effective antiepileptics are: a) the induction of a prolonged inactivation of the Na ϩ channel; b) the blockade of Ca 2ϩ channel currents; c) the enhancement of the inhibitory g-aminobutyrate (GABA)ergic neurotransmission or the modulation of excitatory glutamatergic neurotransmission.3) With respect to this last pharmacological target, extensive studies have demonstrated that competitive and noncompetitive antagonists of the ionotropic glutamate receptors (iGluRs) show promise in terms of their therapeutic potential for the prevention and treatment of the epilepsy. [3][4][5][6][7][8][9][10] In our previous works, some isoquinoline derivatives were found to have anticonvulsant activities in various seizure models interacting with glutamate ionotropic a-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) receptor (AMPAR) subtype in a selective and non-competitive fashion. [11][12][13][14][15][16][17][18][19][20] The most active compound of the series was the 2-acetyl-1-(4Ј-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1, Fig. 1) which showed both in in vivo and in vitro tests activity stronger than other known AMPAR antagonists such as GYKI 52466, talampanel, and CFM-2 (Fig. 1). 17,21,22) Starting from the "lead compound" 1, in several previous studies, we examined a large series of its analogues and reported a comprehensive structure-active relationship (SAR) studies concerning the influence of specific substituents on tetrahydroisoquinoline skeleton; we found that the most active derivatives are generally characterized by the presence of 2-acetyl substituent; moreover two methoxy substituents on the benzene fused ring are crucial to produce pharmacological effects.19) Furthermore our investigations suggested that the introduction of hydrophobic substituents at 4Ј-position of C-1 phenyl moiety (e.g. halogen atoms) could improve the anticonvulsant efficacy against sound-induced seizures in Dilute Brown non-Agouti (DBA/2) mice. These experimental evidences were confirmed by our computational studies in which we developed a 3-D pharmacophore model for noncompetitive AMPAR antagonists.15) Herein we report the sy...

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Section: Resultsmentioning

confidence: 99%

Synthesis and Structure-Active Relationship of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Anticonvulsants

Gitto

Luca

Ferro

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…In order to prepare the demethylated precursors, we envisioned that precursor compounds 11a-d could be prepared by O-demethylation of target compounds 4a-d. A variety of protocols were screened for this purpose including protic acid (HBr), 8 Lewis acids (BBr 3 , AlCl 3 /EtSH), 9,10 and base (EtSNa). 11 However, in all cases, an intractable red solid that could not be characterized or a demethylated product with very low yield was obtained.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis of new carbon‐11‐labeled 7‐aroyl‐aminoindoline‐1‐sulfonamides as potential PET agents for imaging of tubulin polymerization in cancers

Wang

Gao

Miller

et al. 2008

Labelled Comp Radiopharmac

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The tubulin polymerization is an attractive target for anticancer therapy and in the development of cancer imaging agents for use in biomedical imaging technique positron emission tomography (PET). 7-Aroyl-aminoindoline-1-sulfonamides are a novel class of potent antitublin agents. Carbon-11-labeled 7-aroyl-aminoindoline-1-sulfonamides have been synthesized as new potential PET agents for imaging of tubulin polymerization in cancers. The target tracers were prepared by O-[ 11 C]methylation of their corresponding precursors using [11 C]CH 3 OTf and isolated by a simplified solid-phase extraction purification procedure in 40-55% radiochemical yields based on [11 C]CO 2 and decay corrected to the end of bombardment (EOB), 15-20 min overall synthesis time from EOB, >98% radiochemical purity, and 74-111 GBq/lmol specific activity at the end of synthesis.

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“…As an another example, N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3, Fig. 1) has been known to show an antagonistic effect at AMPA [2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid] receptors and known to be useful as a potential neuroprotective agent in the treatment of neurological diseases, such as epilepsy, ischemia, Parkinson's disease, and multiple sclerosis [3,6,7]. Especially, the anticonvulsant effects of 3 were reported to reside mainly in the (R)-enantiomer [8].…”

Section: Introductionmentioning

confidence: 99%

“…For the enantiomeric separation of 1-aryl-1,2,3,4-tetrahydroisoquinolines and/or their derivatives, liquid chromatographic CSPs based on ␤-cyclodextrin [11] or cellulose tris-(3,5-dimethylphenycarbamate) [6,12] have been utilized. However, crown ether-based CSPs have not been utilized in the resolution of 1-aryl-1,2,3,4-tetrahydroisoquinolines.…”

Section: Introductionmentioning

confidence: 99%

Liquid chromatographic resolution of 1-aryl-1,2,3,4-tetrahydroisoquinolines on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

Lee

Jin

Hyun

2011

Journal of Chromatography A

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Synthesis of carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potential PET AMPA receptor ligands

Cited by 53 publications

References 7 publications

Synthesis and Structure-Active Relationship of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Anticonvulsants

Synthesis and Structure-Active Relationship of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Anticonvulsants

Synthesis of new carbon‐11‐labeled 7‐aroyl‐aminoindoline‐1‐sulfonamides as potential PET agents for imaging of tubulin polymerization in cancers

Liquid chromatographic resolution of 1-aryl-1,2,3,4-tetrahydroisoquinolines on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

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