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Bioorg Med Chem. 2014 Mar 1;22(5):1736-50. doi: 10.1016/j.bmc.2014.01.016. Epub 2014 Jan 23.

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

Author information

1
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
2
Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
3
Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
4
PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
5
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.

Abstract

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.

KEYWORDS:

5-HT(7) receptor; Arylpiperazine; PET; Radioligand

PMID:
24508140
DOI:
10.1016/j.bmc.2014.01.016
[Indexed for MEDLINE]
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