Synthesis and evaluation of [¹¹C]Cimbi-806 as a potential PET ligand for 5-HT₇ receptor imaging.
2-(2',6'-Dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT(7)) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]2-(2',6'-dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine ([(11)C]Cimbi-806) as a radioligand for imaging brain 5-HT(7) receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent (11)C-labelling with [(11)C]methyltriflate produced [(11)C]Cimbi-806 in specific activities ranging from 50 to 300 GBq/μmol. Following intravenous injection, brain uptake and distribution of [(11)C]Cimbi-806 was assessed with PET in Danish Landrace pigs. The time-activity curves revealed high brain uptake in thalamic and striatal regions (SUV ∼2.5) and kinetic modeling resulted in distribution volumes (V(T)) ranging from 6 mL/cm(3) in the cerebellum to 12 mL/cm(3) in the thalamus. Pretreatment with the 5-HT(7) receptor antagonist SB-269970 did not result in any significant changes in [(11)C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence of appropriate in vivo blocking with a 5-HT(7) receptor selective compounds renders the conclusion that [(11)C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT(7) receptor in vivo.
Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Matthias M
MM
Herth
Hanne D
HD
Hansen
Anders
A
Ettrup
Agnete
A
Dyssegaard
Szabolcs
S
Lehel
Jesper
J
Kristensen
Gitte M
GM
Knudsen
D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling; D008024:Ligands; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D013552:Swine; D014018:Tissue Distribution
C575893:((11)C)2-(2',6'-dimethoxy-(1,1'-biphenyl)-3-yl)-N,N-dimethylethanamine; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D005021:Ethylamines; D008024:Ligands; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor