Synthesis, radiosynthesis and in vivo preliminary evaluation of [11C]LBT-999, a selective radioligand for the visualisation of the dopamine transporter with PET

Bioorg Med Chem. 2006 Feb 15;14(4):1115-25. doi: 10.1016/j.bmc.2005.09.035. Epub 2005 Oct 10.


LBT-999 (8-((E)-4-fluoro-but-2-enyl)-3beta-p-tolyl-8-aza-bicyclo[3.2.1]octane-2beta-carboxylic acid methyl ester), a cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands, and its corresponding carboxylic acid derivative, the latter used as precursor for labelling both with tritium and the positron-emitter carbon-11 (half-life: 20.38 min), were synthesized from (R)-cocaine. [(3)H]LBT-999 (>99% radiochemically pure, specific radioactivity of 3.1 TBq/mmol) was prepared from [(3)H]methyl iodide, allowing its in vitro pharmacological evaluation (K(D): 9 nM for DAT and IC(50) > 1000 nM for SERT and NET). Routine production batches of 4.5-9.0 GBq of iv injectable solutions of [(11)C]LBT-999 (with specific radioactivities ranging from 30 to 45 GBq/mumol) were prepared in 25-30 min (HPLC purification and formulation included) using the efficient methylation reagent [(11)C]methyl triflate. The preliminary in vivo pharmacological evaluation of [(11)C]LBT-999, using both biodistributions in rats and brain imaging in monkeys with positron emission tomography (PET), clearly illustrates that this ligand is an excellent candidate for quantification with PET of DAT in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / metabolism*
  • Carbon Radioisotopes
  • Cocaine / analogs & derivatives
  • Dopamine Plasma Membrane Transport Proteins / chemistry*
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Esters / chemical synthesis*
  • Esters / chemistry
  • Esters / metabolism*
  • Molecular Structure
  • Nortropanes
  • Papio
  • Positron-Emission Tomography / methods*
  • Radioligand Assay
  • Sensitivity and Specificity
  • Structure-Activity Relationship
  • Substrate Specificity


  • 8-((E)-4-fluoro-but-2-enyl)-3beta-p-tolyl-8-aza-bicyclo(3.2.1)octane-2beta-carboxylic acid methyl ester
  • Bridged Bicyclo Compounds
  • Carbon Radioisotopes
  • Dopamine Plasma Membrane Transport Proteins
  • Esters
  • Nortropanes
  • Cocaine