Synthesis of carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium derivatives as new potential PET SKCa channel imaging agents

Mingzhang Gao, Min Wang, Qi-Huang Zheng

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Small conductance Ca2+-activated K+ (SKCa) channels play an important role in many functions such as neuronal communication and behavioral plasticity, secretion, and cell proliferation. SKCa channel modulation is associated with various brain, heart, and cancer diseases. N-methyl-laudanosine and its structurally related derivatives, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums, are reversible and selective SKCa channel blockers. Carbon-11 labeled N-methyl-laudanosine and its tetrahydroisoquinolinium derivatives may serve as new probes for positron emission tomography (PET) to image SKCa channels in the brain, heart, and cancer. The key intermediates, substituted isoquinolines (3a-c), were synthesized using a modification of the Pomeranz-Fritsch procedure. The precursors, substituted 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolines (8a-c), and their corresponding reference standards, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums (9a-c), were synthesized from compounds 3a-c with 3,4-dimethoxybenzyl chloride (2) in multiple steps with moderate to excellent chemical yields. The precursor 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (10) was commercially available, and the methylation of compound 10 with methyl iodide provided N-methyl-laudanosine (11). The target quaternary ammonium tracers, carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums ([11C]9a-c and [11C]11), were prepared by N-[11C]methylation of the tertiary amine precursors (8a-c and 10) with [11C]methyl triflate and isolated by a simplified solid-phase extraction (SPE) purification using a SiO2 or cation-exchange CM Sep-Pak cartridge in 40-65% radiochemical yields.

Original languageEnglish
Pages (from-to)194-202
Number of pages9
JournalApplied Radiation and Isotopes
Volume66
Issue number2
DOIs
StatePublished - Feb 2008

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Keywords

  • 1-(3,4-Dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums
  • Carbon-11
  • Imaging
  • N-methyl-laudanosine
  • Positron emission tomography (PET)
  • Small conductance Ca-activated K (SKCa) channels

ASJC Scopus subject areas

  • Radiation

Cite this

@article{9d4335691a1d44ddb5826ebbaf23dee9,
title = "Synthesis of carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium derivatives as new potential PET SKCa channel imaging agents",
abstract = "Small conductance Ca2+-activated K+ (SKCa) channels play an important role in many functions such as neuronal communication and behavioral plasticity, secretion, and cell proliferation. SKCa channel modulation is associated with various brain, heart, and cancer diseases. N-methyl-laudanosine and its structurally related derivatives, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums, are reversible and selective SKCa channel blockers. Carbon-11 labeled N-methyl-laudanosine and its tetrahydroisoquinolinium derivatives may serve as new probes for positron emission tomography (PET) to image SKCa channels in the brain, heart, and cancer. The key intermediates, substituted isoquinolines (3a-c), were synthesized using a modification of the Pomeranz-Fritsch procedure. The precursors, substituted 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolines (8a-c), and their corresponding reference standards, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums (9a-c), were synthesized from compounds 3a-c with 3,4-dimethoxybenzyl chloride (2) in multiple steps with moderate to excellent chemical yields. The precursor 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (10) was commercially available, and the methylation of compound 10 with methyl iodide provided N-methyl-laudanosine (11). The target quaternary ammonium tracers, carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums ([11C]9a-c and [11C]11), were prepared by N-[11C]methylation of the tertiary amine precursors (8a-c and 10) with [11C]methyl triflate and isolated by a simplified solid-phase extraction (SPE) purification using a SiO2 or cation-exchange CM Sep-Pak cartridge in 40-65{\%} radiochemical yields.",
keywords = "1-(3,4-Dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums, Carbon-11, Imaging, N-methyl-laudanosine, Positron emission tomography (PET), Small conductance Ca-activated K (SKCa) channels",
author = "Mingzhang Gao and Min Wang and Qi-Huang Zheng",
year = "2008",
month = "2",
doi = "10.1016/j.apradiso.2007.08.011",
language = "English",
volume = "66",
pages = "194--202",
journal = "Applied Radiation and Isotopes",
issn = "0969-8043",
publisher = "Elsevier Limited",
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TY - JOUR

T1 - Synthesis of carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium derivatives as new potential PET SKCa channel imaging agents

AU - Gao, Mingzhang

AU - Wang, Min

AU - Zheng, Qi-Huang

PY - 2008/2

Y1 - 2008/2

N2 - Small conductance Ca2+-activated K+ (SKCa) channels play an important role in many functions such as neuronal communication and behavioral plasticity, secretion, and cell proliferation. SKCa channel modulation is associated with various brain, heart, and cancer diseases. N-methyl-laudanosine and its structurally related derivatives, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums, are reversible and selective SKCa channel blockers. Carbon-11 labeled N-methyl-laudanosine and its tetrahydroisoquinolinium derivatives may serve as new probes for positron emission tomography (PET) to image SKCa channels in the brain, heart, and cancer. The key intermediates, substituted isoquinolines (3a-c), were synthesized using a modification of the Pomeranz-Fritsch procedure. The precursors, substituted 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolines (8a-c), and their corresponding reference standards, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums (9a-c), were synthesized from compounds 3a-c with 3,4-dimethoxybenzyl chloride (2) in multiple steps with moderate to excellent chemical yields. The precursor 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (10) was commercially available, and the methylation of compound 10 with methyl iodide provided N-methyl-laudanosine (11). The target quaternary ammonium tracers, carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums ([11C]9a-c and [11C]11), were prepared by N-[11C]methylation of the tertiary amine precursors (8a-c and 10) with [11C]methyl triflate and isolated by a simplified solid-phase extraction (SPE) purification using a SiO2 or cation-exchange CM Sep-Pak cartridge in 40-65% radiochemical yields.

AB - Small conductance Ca2+-activated K+ (SKCa) channels play an important role in many functions such as neuronal communication and behavioral plasticity, secretion, and cell proliferation. SKCa channel modulation is associated with various brain, heart, and cancer diseases. N-methyl-laudanosine and its structurally related derivatives, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums, are reversible and selective SKCa channel blockers. Carbon-11 labeled N-methyl-laudanosine and its tetrahydroisoquinolinium derivatives may serve as new probes for positron emission tomography (PET) to image SKCa channels in the brain, heart, and cancer. The key intermediates, substituted isoquinolines (3a-c), were synthesized using a modification of the Pomeranz-Fritsch procedure. The precursors, substituted 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolines (8a-c), and their corresponding reference standards, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums (9a-c), were synthesized from compounds 3a-c with 3,4-dimethoxybenzyl chloride (2) in multiple steps with moderate to excellent chemical yields. The precursor 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (10) was commercially available, and the methylation of compound 10 with methyl iodide provided N-methyl-laudanosine (11). The target quaternary ammonium tracers, carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums ([11C]9a-c and [11C]11), were prepared by N-[11C]methylation of the tertiary amine precursors (8a-c and 10) with [11C]methyl triflate and isolated by a simplified solid-phase extraction (SPE) purification using a SiO2 or cation-exchange CM Sep-Pak cartridge in 40-65% radiochemical yields.

KW - 1-(3,4-Dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums

KW - Carbon-11

KW - Imaging

KW - N-methyl-laudanosine

KW - Positron emission tomography (PET)

KW - Small conductance Ca-activated K (SKCa) channels

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U2 - 10.1016/j.apradiso.2007.08.011

DO - 10.1016/j.apradiso.2007.08.011

M3 - Article

C2 - 17905592

AN - SCOPUS:37149043294

VL - 66

SP - 194

EP - 202

JO - Applied Radiation and Isotopes

JF - Applied Radiation and Isotopes

SN - 0969-8043

IS - 2

ER -