title: Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates.
abstract: BACKGROUND
  Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug.
  
  
  METHODS
  The drugs were radiolabeled with (11)C (t 1/2 = 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (KP) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (VT). Unbound KP (KP u,u) was obtained by correction for the free fraction in brain and plasma.
  
  
  RESULTS
  After intravenous injection, the maximum radioactivity concentration (C max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C max, %ID was >2%, indicating a preferential distribution to brain. A lower C max, %ID was observed for morphine, sulpiride, and verapamil. K P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had KP u,u close to unity. For morphine, sulpiride, and verapamil, K P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs.
  
  
  CONCLUSIONS
  This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist). magnus.schou@astrazeneca.com.
authors: Magnus
authors: M
authors: Schou
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Katarina
authors: K
authors: Varnäs
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Stefan
authors: S
authors: Lundquist
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Ryuji
authors: R
authors: Nakao
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Nahid
authors: N
authors: Amini
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Akihiro
authors: A
authors: Takano
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Sjoerd J
authors: SJ
authors: Finnema
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Christer
authors: C
authors: Halldin
authors: AstraZeneca Translational Science Centre at Karolinska Institutet, Stockholm, Sweden (Drs Schou and Farde); Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Varnäs, Lundquist, Nakao, Amini, Takano, Finnema, and Halldin); AstraZeneca, Innovative Medicines, CNS & Pain, Södertälje, Sweden (Dr Lundquist).
authors: Lars
authors: L
authors: Farde
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008954:Models, Biological; D008956:Models, Chemical; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013469:Sulpiride / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D002250:Carbon Radioisotopes; D002491:Central Nervous System Agents; D019275:Radiopharmaceuticals; D009020:Morphine; D013469:Sulpiride; D014700:Verapamil
keywords: CNS; PET; microdosing