Synthesis, radiolabeling and in vivo evaluation of [(11)C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT(7) receptor

Hanne D Hansen; Enza Lacivita; Pantaleo Di Pilato; Matthias M Herth; Szabolcs Lehel; Anders Ettrup; Valdemar L Andersen; Agnete Dyssegaard; Paola De Giorgio; Roberto Perrone; Francesco Berardi; Nicola Antonio Colabufo; Mauro Niso; Gitte M Knudsen; Marcello Leopoldo

doi:10.1016/j.ejmech.2014.03.066

Synthesis, radiolabeling and in vivo evaluation of [(11)C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT(7) receptor

Eur J Med Chem. 2014 May 22:79:152-63. doi: 10.1016/j.ejmech.2014.03.066. Epub 2014 Mar 29.

Authors

Affiliations

¹ Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
² Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
³ Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, 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 Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. Electronic address: gmk@nru.dk.

PMID: 24732791
DOI: 10.1016/j.ejmech.2014.03.066

Abstract

In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [(11)C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [(11)C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands.

Keywords: 5-HT(7) receptor; Arylpiperazine; PET; Radioligand; SB-269970.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / diagnostic imaging
CHO Cells
Carbon Isotopes
Cricetulus
HEK293 Cells
Humans
Kinetics
Ligands
Molecular Structure
Phenols / pharmacology
Piperazines / chemical synthesis*
Piperazines / chemistry
Positron-Emission Tomography*
Propanols / chemical synthesis*
Propanols / chemistry
Pyrazines / chemical synthesis*
Pyrazines / chemistry
Radiopharmaceuticals* / chemical synthesis
Radiopharmaceuticals* / pharmacokinetics
Receptors, Serotonin / metabolism*
Sulfonamides / pharmacology
Swine
Tissue Distribution

Substances

((11)C)(R)-1-(4-(2-(4-methoxyphenyl)phenyl)piperazin-1-yl)-3-(2-pyrazinyloxy)-2-propanol
Carbon Isotopes
Ligands
Phenols
Piperazines
Propanols
Pyrazines
Radiopharmaceuticals
Receptors, Serotonin
SB 269970
Sulfonamides
serotonin 7 receptor