Synthesis and radiopharmacological characterization of 2beta-carbo-2'-[18F]fluoroethoxy-3beta-(4-bromo-phenyl)tropane ([18F]MCL-322) as a PET radiotracer for imaging the dopamine transporter (DAT)

Bioorg Med Chem. 2007 Jul 1;15(13):4511-9. doi: 10.1016/j.bmc.2007.04.019. Epub 2007 Apr 19.

Abstract

The fluoroalkyl-containing tropane derivative 2beta-carbo-2'-fluoroethoxy-3beta-(4-bromo-phenyl)tropane (MCL-322) is a highly potent and moderately selective ligand for the dopamine transporter (DAT). The compound was labeled with the short-lived positron emitter (18)F in a single step by nucleophilic displacement of the corresponding tosylate precursor MCL-323 with no-carrier-added [(18)F]fluoride. The positron emission tomography (PET) radiotracer 2beta-carbo-2'-[(18)F]fluoroethoxy-3beta-(4-bromo-phenyl)tropane [(18)F]MCL-322 was obtained in decay-corrected radiochemical yields of 30-40% at a specific radioactivity of 1.6-2.4Ci/mumol (60-90GBq/mumol) at the end-of-synthesis (EOS). Small animal PET, ex vivo and in vivo biodistribution experiments in rats demonstrated a high uptake in the striatum (3.2% ID/g) 5min after injection, which increased to 4.2% ID/g after 60min. The uptake in the cerebellum was 1.8% ID/g and 0.6% ID/g after 5min and 60min post-injection, respectively. Specific binding to DAT of [(18)F]MCL-322 was confirmed by blocking experiments using the high affinity DAT ligand GBR 12909. The radiopharmacological characterization was completed with metabolite and autoradiographic studies confirming the selective uptake of [(18)F]MCL-322 in the striatum. It is concluded that the simple single-step radiosynthesis of [(18)F]MCL-322 and the promising radiopharmacological data make [(18)F]MCL-322 an attractive candidate for the further development of a PET radiotracer potentially suitable for clinical DAT imaging in the human brain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoradiography
  • Binding, Competitive / drug effects
  • Biotransformation
  • Brain / diagnostic imaging
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Isotope Labeling
  • Magnetic Resonance Imaging
  • Male
  • Piperazines / pharmacology
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Tissue Distribution
  • Tropanes / chemical synthesis*
  • Tropanes / pharmacology

Substances

  • 2beta-carbo-2'-(18F)fluoroethoxy-3beta-(4-bromo-phenyl)tropane
  • Dopamine Plasma Membrane Transport Proteins
  • Piperazines
  • Radiopharmaceuticals
  • Tropanes
  • vanoxerine