Serotonin 2A receptor agonist binding in the human brain with [¹¹C]Cimbi-36.
[(11)C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT(2A)) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [(11)C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT(2A) receptors with [(11)C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [(11)C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [(11)C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT(2A) receptor antagonist ketanserin before a second PET scan significantly decreased [(11)C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [(11)C]Cimbi-36 binding is selective for 5-HT(2A) receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT(2A) receptors in the human brain. Thus, we here describe [(11)C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT(2A) receptors in the human brain.
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Anders
A
Ettrup
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Sophie
S
da Cunha-Bang
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Brenda
B
McMahon
PET- and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Szabolcs
S
Lehel
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Agnete
A
Dyssegaard
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Anine W
AW
Skibsted
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Louise M
LM
Jørgensen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Martin
M
Hansen
Department of Radiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Anders O
AO
Baandrup
Department of Neuroanaesthesiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Søren
S
Bache
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Claus
C
Svarer
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jesper L
JL
Kristensen
PET- and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Nic
N
Gillings
PET- and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Jacob
J
Madsen
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Gitte M
GM
Knudsen
D001596:Benzylamines / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging*; D005260:Female; D006801:Humans; D008297:Male; D010627:Phenethylamines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D044402:Receptor, Serotonin, 5-HT2A / Q000032:analysis* / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000493:pharmacokinetics*; D055815:Young Adult
D001596:Benzylamines; C586246:Cimbi-36; D010627:Phenethylamines; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists