Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging

BMC Med Imaging. 2007 Jul 30;7:6. doi: 10.1186/1471-2342-7-6.

Abstract

Background: The previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171.

Methods: [1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/mumol and 270 GBq/mumol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171.

Results: All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171.

Conclusion: The propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl-analogue (I).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Radioisotopes / chemistry
  • Carbon Radioisotopes / pharmacokinetics
  • Corpus Striatum / diagnostic imaging*
  • Corpus Striatum / metabolism*
  • Drug Design
  • Feasibility Studies
  • Guinea Pigs
  • Hydrocarbons, Iodinated / pharmacokinetics*
  • Isotope Labeling / methods
  • Macaca mulatta
  • Male
  • Metabolic Clearance Rate
  • Pilot Projects
  • Piperidines / pharmacokinetics
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics
  • Receptors, Neurokinin-1 / metabolism*
  • Tetrazoles / pharmacokinetics
  • Tissue Distribution

Substances

  • Carbon Radioisotopes
  • Hydrocarbons, Iodinated
  • Piperidines
  • Radiopharmaceuticals
  • Receptors, Neurokinin-1
  • Tetrazoles
  • vofopitant
  • propyl iodide