title: Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers.
abstract: OBJECTIVE
  Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig brain.
  
  
  METHODS
  Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT(2A) receptor binding, cortical nondisplaceable binding potentials (BP(ND)) were calculated using the simplified reference tissue model with the cerebellum as a reference region.
  
  
  RESULTS
  After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT(2A) receptor distribution. The largest target-to-background binding ratio was found for [(11)C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [(11)C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT(2A) receptor selectivity in vivo. [(11)C]Cimbi-82 and [(11)C]Cimbi-21 showed lower cortical BP(ND), while [(11)C]Cimbi-27, [(11)C]Cimbi-29, [(11)C]Cimbi-31 and [(11)C]Cimbi-88 gave rise to cortical BP(ND) similar to that of [(11)C]Cimbi-5.
  
  
  CONCLUSIONS
  [(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, building 9201, DK-2100, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Ettrup
authors.forename: Martin
authors.initials: M
authors.lastname: Hansen
authors.forename: Martin A
authors.initials: MA
authors.lastname: Santini
authors.forename: James
authors.initials: J
authors.lastname: Paine
authors.forename: Nic
authors.initials: N
authors.lastname: Gillings
authors.forename: Mikael
authors.initials: M
authors.lastname: Palner
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Herth
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.forename: Jesper
authors.initials: J
authors.lastname: Kristensen
authors.forename: Mikael
authors.initials: M
authors.lastname: Begtrup
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007275:Injections, Intravenous; D007650:Ketanserin / Q000494:pharmacology; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011854:Radiochemistry; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013552:Swine
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; C586246:Cimbi-36; D010627:Phenethylamines; D010716:Phosphatidylinositols; D011849:Radioactive Tracers; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; C029261:phenethylamine; D007650:Ketanserin