Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Benzofurans / chemical synthesis*
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Benzofurans / chemistry
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Benzofurans / pharmacokinetics
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Binding, Competitive
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Brain / diagnostic imaging
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Brain / metabolism*
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Drug Stability
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Fluorine Radioisotopes
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HEK293 Cells
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Histamine Agonists / chemical synthesis
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Histamine Agonists / chemistry
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Histamine Agonists / pharmacokinetics
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Histamine Antagonists / chemical synthesis
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Histamine Antagonists / chemistry
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Histamine Antagonists / pharmacokinetics
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Humans
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Ligands
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Macaca mulatta
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Male
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Mice
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Molecular Imaging
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Positron-Emission Tomography
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacokinetics
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Radiopharmaceuticals / chemical synthesis*
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Radiopharmaceuticals / chemistry
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Radiopharmaceuticals / pharmacokinetics
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Receptors, Histamine H3 / metabolism*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Benzofurans
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Fluorine Radioisotopes
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Histamine Agonists
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Histamine Antagonists
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Ligands
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Pyrrolidines
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Radiopharmaceuticals
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Receptors, Histamine H3