title: Synthesis, structure-affinity relationships, and radiolabeling of selective high-affinity 5-HT4 receptor ligands as prospective imaging probes for positron emission tomography.
abstract: In a search for high-affinity receptor ligands that might serve for development as radioligands for the imaging of brain 5-HT(4) receptors in vivo with positron emission tomography (PET), structural modifications were made to the high-affinity 5-HT(4) antagonist (1-butylpiperidin-4-yl)methyl 8-amino-7-iodo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate (1, SB 207710). These modifications were made mainly on the aryl side of the ester bond to permit possible rapid labeling of the carboxylic acid component with a positron emitter, either carbon-11 (t(1/2) = 20.4 min) or fluorine-18 (t(1/2) = 109.7 min), and included (i) replacement of the iodine atom with a small substituent such as nitrile, methyl, or fluoro, (ii) methylation of the 8-amino group, (iii) opening of the dioxan ring, and (iv) alteration of the length of the N-alkyl goup. High-affinity ligands were discovered for recombinant human 5-HT(4) receptors with amenability to labeling with a positron emitter and potential for development as imaging probes. The ring-opened radioligand, (([methoxy-(11)C]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [(11)C]13), showed an especially favorable array of properties for future evaluation as a PET radioligand for brain 5-HT(4) receptors.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Morse
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D002460:Cell Line; D006224:Cricetinae; D054314:Drug Inverse Agonism; D054333:Drug Partial Agonism; D005462:Fluorine Radioisotopes; D006168:Guinea Pigs; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D013045:Species Specificity; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates
chemical_list: C553286:(1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D062366:para-Aminobenzoates; D044422:Receptors, Serotonin, 5-HT4; D010129:4-Aminobenzoic Acid
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