[11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

Nucl Med Biol. 2014 Oct;41(9):758-64. doi: 10.1016/j.nucmedbio.2014.06.004. Epub 2014 Jun 25.

Abstract

Introduction: Positron emission tomography (PET) imaging of the norepinephrine transporter (NET) is still hindered by the availability of useful PET imaging probes. The present study describes the radiosynthesis and pre-clinical evaluation of a new compound, exo-3-(6-methoxypyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine.

Methods: Labeling of NS8880 with [(11)C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [(11)C]methanolate in a Boc-protected precursor. The isolated [(11)C]NS8880 was evaluated pre-clinically both in a pig model (PET scanning) and in a rat model (μPET scanning) and compared to (S,S)-[(11)C]-O-methylreboxetine ([(11)C]MeNER).

Results: The radiolabeling technique yielded [(11)C]NS8880 in low (<10%) but still useful yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [(11)C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [(11)C]NS8880.

Conclusion: Based on the pre-clinical results obtained so far [(11)C]NS8880 displays promising properties for PET imaging of NET.

Keywords: MeNER; NS8880; Norepinephrine transporter; PET; Preclinical evaluation; Radiosynthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging*
  • Brain / metabolism*
  • Carbon Radioisotopes / chemistry
  • Carbon Radioisotopes / pharmacokinetics
  • Female
  • Isotope Labeling / methods
  • Male
  • Molecular Imaging / methods*
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism*
  • Octanes / chemical synthesis
  • Octanes / pharmacokinetics*
  • Organ Specificity
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Swine
  • Tissue Distribution

Substances

  • Carbon Radioisotopes
  • Norepinephrine Plasma Membrane Transport Proteins
  • Octanes
  • Radiopharmaceuticals