title: Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[(11)C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors.
abstract: BACKGROUND
  The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor.
  
  
  METHODS
  N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats.
  
  
  RESULTS
  N-((5-(4-fluoro-2-[(11)C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49±3% (decay-corrected) yield, affording 4.1±0.3 GBq of formulated product at the end of synthesis with a radiochemical purity of >99% and with a specific activity of 78±10 GBq/μmol.
  
  
  CONCLUSIONS
  A new NR2B PET ligand was developed in high yield. [(11)C]4 readily enters the brain and binds to the NR2B subunit-containing NMDAr in the rodent brain. High sigma-1 receptor binding may, however, limit its future application as a PET probe for imaging the NR2B subunit-containing NMDAr. Anaesthesia has an effect on NMDAr function and therefore can complicate interpretation of preclinical in vivo results. In addition, effects of endogenous compounds cannot be excluded. Despite these potential limitations, further studies are warranted to investigate the values of [(11)C]4 as an NR2B PET ligand.
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Johannes A M
authors.initials: JA
authors.lastname: Christiaans
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Klein
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Metaxas
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Esther J M
authors.initials: EJ
authors.lastname: Kooijman
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Schuit
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Josée E
authors.initials: JE
authors.lastname: Leysen
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bart N M
authors.initials: BN
authors.lastname: van Berckel
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands. Electronic address: ad.windhorst@vumc.nl.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008297:Male; D051379:Mice; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D011854:Radiochemistry; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D002250:Carbon Radioisotopes; D003517:Cyclopentanes; D008024:Ligands; C000595850:N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981
keywords: Carbon-11; NR2B; PET