Synthesis and evaluation of [11C]Cimbi-806 as a potential PET ligand for 5-HT₇ receptor imaging

TY - JOUR

T1 - Synthesis and evaluation of [11C]Cimbi-806 as a potential PET ligand for 5-HT7 receptor imaging

AU - Herth, Matthias Manfred

AU - Hansen, Hanne Demant

AU - Ettrup, Anders Janusz

AU - Dyssegaard, Agnete

AU - Lehel, Szabolcs

AU - Kristensen, Jesper Langgaard

AU - Knudsen, Gitte Moos

PY - 2012/7/15

Y1 - 2012/7/15

N2 - 2-(2′,6′-Dimethoxy-[1,1′-biphenyl]-3-yl)-N, N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT7) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [11C]2-(2′,6′- dimethoxy-[1,1′-biphenyl]-3-yl)-N,N-dimethylethanamine ([ 11C]Cimbi-806) as a radioligand for imaging brain 5-HT7 receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent 11C-labelling with [ 11C]methyltriflate produced [11C]Cimbi-806 in specific activities ranging from 50 to 300 GBq/μmol. Following intravenous injection, brain uptake and distribution of [11C]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 (VT) ranging from 6 mL/cm3 in the cerebellum to 12 mL/cm3 in the thalamus. Pretreatment with the 5-HT7 receptor antagonist SB-269970 did not result in any significant changes in [11C]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-HT7 receptor selective compounds renders the conclusion that [11C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT7 receptor in vivo.

AB - 2-(2′,6′-Dimethoxy-[1,1′-biphenyl]-3-yl)-N, N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT7) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [11C]2-(2′,6′- dimethoxy-[1,1′-biphenyl]-3-yl)-N,N-dimethylethanamine ([ 11C]Cimbi-806) as a radioligand for imaging brain 5-HT7 receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent 11C-labelling with [ 11C]methyltriflate produced [11C]Cimbi-806 in specific activities ranging from 50 to 300 GBq/μmol. Following intravenous injection, brain uptake and distribution of [11C]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 (VT) ranging from 6 mL/cm3 in the cerebellum to 12 mL/cm3 in the thalamus. Pretreatment with the 5-HT7 receptor antagonist SB-269970 did not result in any significant changes in [11C]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-HT7 receptor selective compounds renders the conclusion that [11C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT7 receptor in vivo.

U2 - 10.1016/j.bmc.2012.05.005

DO - 10.1016/j.bmc.2012.05.005

M3 - Journal article

C2 - 22682922

SN - 0968-0896

VL - 20

SP - 4574

EP - 4581

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 14

ER -