A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis

Hyla Allouche-Arnon, Ayelet Gamliel, Claudia M. Barzilay, Ruppen Nalbandian, J. Moshe Gomori, Magnus Karlsson, Mathilde Hauge Lerche, Rachel Katz-Brull

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Choline as a reporter molecule has been investigated by in vivo magnetic resonance for almost three decades. Accumulation of choline metabolites (mainly the phosphorylated forms) had been observed in malignancy in preclinical models, ex-vivo, in vivo and in patients. The combined choline metabolite signal appears in H-1-MRS of the brain and its relative intensity had been used as a diagnostic factor in various conditions. The advent of spin hyperpolarization methods for in vivo use has raised interest in the ability to follow the physiological metabolism of choline into acetylcholine in the brain. Here we present a stable-isotope labeled choline analog, [1,1,2,2-D-4,2-C-13]choline chloride, that is suitable for this purpose. In this analog, the C-13 position showed 24% polarization in the liquid state, following DNP hyperpolarization. This nucleus also showed a long T-1 (35 s) at 11.8 T and 25 degrees C, which is a prerequisite for hyperpolarized studies. The chemical shift of this C-13 position differentiates choline and acetylcholine from each other and from the other water-soluble choline metabolites, namely phosphocholine and betaine. Enzymatic studies using an acetyltransferase enzyme showed the synthesis of the deuterated-acetylcholine form at thermal equilibrium conditions and in a hyperpolarized state. Analysis using a comprehensive model showed that the T-1 of the formed hyperpolarized [1,1,2,2-D-4,2-C-13]acetylcholine was 34 s at 14.1 T and 37 degrees C. We conclude that [1,1,2,2-D-4,2-C-13]choline chloride is a promising new molecular probe for hyperpolarized metabolic studies and discuss the factors related to its possible use in vivo. Copyright (C) 2010 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article.
Original languageEnglish
JournalContrast Media & Molecular Imaging
Volume6
Issue number3
Pages (from-to)139-147
ISSN1555-4309
DOIs
Publication statusPublished - 2011
Externally publishedYes

Keywords

  • Acetylcholine
  • Animals
  • Betaine
  • Brain Chemistry
  • Choline
  • Humans
  • Magnetic Resonance Spectroscopy
  • Metabolomics
  • Molecular Probes
  • Phosphorylcholine
  • Radiology, Nuclear Medicine and Imaging
  • Deuterium
  • Hyperpolarization
  • Kinetic model
  • Magnetic resonance
  • Spin-lattice relaxation
  • acetylcholine
  • acyltransferase
  • betaine
  • carbon 13
  • choline
  • choline chloride c 13
  • choline derivative
  • phosphorylcholine
  • unclassified drug
  • article
  • human
  • hyperpolarization
  • metabolite
  • molecular probe
  • nuclear magnetic resonance spectroscopy
  • priority journal
  • reaction analysis
  • synthesis
  • RADIOLOGY,
  • MAGNETIC-RESONANCE-SPECTROSCOPY
  • BREAST-CANCER CELLS
  • IN-VIVO
  • RELAXATION-TIMES
  • CDP-CHOLINE
  • ACETYLTRANSFERASE
  • METABOLISM
  • RELEASE
  • NMR
  • HIPPOCAMPUS
  • magnetic resonance
  • deuterium
  • kinetic model
  • spin-lattice relaxation

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