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Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor

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  1. Convergent (18)F-labeling and evaluation of N-benzyl-phenethylamines as 5-HT2A receptor PET ligands

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

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  1. Prevalence of cognitive impairment and its relation to mental health in Danish lymphoma survivors

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  2. A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABAA receptors

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  3. Nondisplaceable Binding Is a Potential Confounding Factor in 11C-PBR28 Translocator Protein PET Studies

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  4. Reward processing in major depressive disorder and prediction of treatment response - Neuropharm study

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Here we describe the design, synthesis, and pharmacological evaluation of a set of compounds structurally related to the high affinity serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT1A and adrenergic α1 receptors. The synthesized compounds have chemical features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomography (PET) analysis revealed that [(11)C]-23a and [(11)C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Volume22
Issue number5
Pages (from-to)1736-1750
ISSN0968-0896
DOIs
Publication statusPublished - 23 Jan 2014

ID: 42924647