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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.

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Lacivita E,Niso M,Hansen HD,Di Pilato P,Herth MM,Lehel S,Ettrup A,Montenegro L,Perrone R,Berardi F,Colabufo NA,Leopoldo M,Knudsen GM

doi

10.1016/j.bmc.2014.01.016

subject

Has Abstract

pub_date

2014-03-01 00:00:00

pages

1736-50

issue

5

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(14)00044-3

journal_volume

22

pub_type

杂志文章

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