title: [11C]AF150(S), an agonist PET ligand for M1 muscarinic acetylcholine receptors.
abstract: BACKGROUND
  The M1 muscarinic acetylcholine receptor (M1ACh-R) is a G protein-coupled receptor that can occur in interconvertible coupled and uncoupled states. It is enriched in the basal ganglia, hippocampus, olfactory bulb, and cortical areas, and plays a role in motor and cognitive functions. Muscarinic M1 agonists are potential therapeutic agents for cognitive disorders. The aim of this study was to evaluate [11C]AF150(S) as a putative M1ACh-R agonist PET ligand, which, owing to its agonist properties, could provide a tool to explore the active G protein-coupled receptor.
  
  
  METHODS
  Regional kinetics of [11C]AF150(S) in rat brain were measured using a high-resolution research tomograph, both under baseline conditions and following pre-treatment with various compounds or co-administration of non-radioactive AF150(S). Data were analysed by calculating standard uptake values and by applying the simplified reference tissue model (SRTM).
  
  
  RESULTS
  [11C]AF150(S) was rapidly taken up in the brain, followed by a rapid clearance from all brain regions. Analysis of PET data using SRTM revealed a binding potential (BPND) of 0.25 for the striatum, 0.20 for the hippocampus, 0.16 for the frontal cortical area and 0.15 for the posterior cortical area, all regions rich in M1ACh-R. BPND values were significantly reduced following pre-treatment with M1ACh-R antagonists. BPND values were not affected by pre-treatment with a M3ACh-R antagonist. Moreover, BPND was significantly reduced after pre-treatment with haloperidol, a dopamine D2 receptor blocker that causes an increase in extracellular acetylcholine (ACh). The latter may compete with [11C]AF150(S) for binding to the M1ACh-R; further pharmacological agents were applied to investigate this possibility. Upon injection of the highest dose (49.1 nmol kg-1) of [11C]AF150(S) diluted with non-radioactive AF150(S), brain concentration of AF150(S) reached 100 nmol L-1 at peak level. At this concentration, no sign of saturation in binding to M1ACh-R was observed.
  
  
  CONCLUSIONS
  The agonist PET ligand [11C]AF150(S) was rapidly taken up in the brain and showed an apparent specific M1ACh-R-related signal in brain areas that are rich in M1ACh-R. Moreover, binding of the agonist PET ligand [11C]AF150(S) appears to be sensitive to changes in extracellular ACh levels. Further studies are needed to evaluate the full potential of [11C]AF150(S) for imaging the active pool of M1ACh-R in vivo.
authors.affiliation: Department of Nuclear Medicine & PET Research, VU University Medical Center, PO Box 7057, Amsterdam, , 1007 MB, The Netherlands. HJC.Buiter@vumc.nl.
authors.forename: Hans Jc
authors.initials: HJ
authors.lastname: Buiter
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.forename: Marc C
authors.initials: MC
authors.lastname: Huisman
authors.forename: Maqsood
authors.initials: M
authors.lastname: Yaqub
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Knol
authors.forename: Abraham
authors.initials: A
authors.lastname: Fisher
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Josée E
authors.initials: JE
authors.lastname: Leysen