Radiosynthesis and evaluation of an (18)F-labeled positron emission tomography (PET) radioligand for brain histamine subtype-3 receptors based on a nonimidazole 2-aminoethylbenzofuran chemotype.
A known chemotype of H(3) receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H(3)) receptors in vivo with positron emission tomography (PET), namely nonimidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)methanone (9). Compound 9 was labeled with fluorine-18 (t(1/2) = 109.7 min) in high specific activity by treating the prepared nitro analogue (12) with cyclotron-produced [(18)F]fluoride ion. [(18)F]9 was studied with PET in mouse and in monkey after intravenous injection. [(18)F]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H(3) receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H(3) receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands.
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, USA.
Xiaofeng
X
Bao
Shuiyu
S
Lu
Jeih-San
JS
Liow
Sami S
SS
Zoghbi
Kimberly J
KJ
Jenko
David T
DT
Clark
Robert L
RL
Gladding
Robert B
RB
Innis
Victor W
VW
Pike
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D057809:HEK293 Cells; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D057054:Molecular Imaging; D049268:Positron-Emission Tomography; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001572:Benzofurans; D005462:Fluorine Radioisotopes; D017442:Histamine Agonists; D006633:Histamine Antagonists; D008024:Ligands; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3