Synthesis, radiolabeling and in vivo evaluation of [11C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor

Hanne Demant 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 [¹¹C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor

Hanne Demant 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

16 Citations (Scopus)

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.

Original language	English
Journal	European Journal of Medicinal Chemistry
Volume	79
Pages (from-to)	152-163
Number of pages	12
ISSN	0223-5234
DOIs	https://doi.org/10.1016/j.ejmech.2014.03.066
Publication status	Published - 22 May 2014

Keywords

Animals
Brain
CHO Cells
Carbon Isotopes
Cricetulus
HEK293 Cells
Humans
Kinetics
Ligands
Molecular Structure
Phenols
Piperazines
Positron-Emission Tomography
Propanols
Pyrazines
Radiopharmaceuticals
Receptors, Serotonin
Sulfonamides
Swine
Tissue Distribution

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10.1016/j.ejmech.2014.03.066

Cite this

Hansen, H. D., Lacivita, E., Di Pilato, P., Herth, M. M., Lehel, S., Ettrup, A., Andersen, V. L., Dyssegaard, A., De Giorgio, P., Perrone, R., Berardi, F., Colabufo, N. A., Niso, M., Knudsen, G. M., & Leopoldo, M. (2014). Synthesis, radiolabeling and in vivo evaluation of [¹¹C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor. European Journal of Medicinal Chemistry, 79, 152-163. https://doi.org/10.1016/j.ejmech.2014.03.066

Synthesis, radiolabeling and in vivo evaluation of [¹¹C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor. / Hansen, Hanne Demant; Lacivita, Enza; Di Pilato, Pantaleo et al.
In: European Journal of Medicinal Chemistry, Vol. 79, 22.05.2014, p. 152-163.

Research output: Contribution to journal › Journal article › Research › peer-review

Hansen, HD, Lacivita, E, Di Pilato, P, Herth, MM, Lehel, S, Ettrup, A, Andersen, VL, Dyssegaard, A, De Giorgio, P, Perrone, R, Berardi, F, Colabufo, NA, Niso, M, Knudsen, GM & Leopoldo, M 2014, 'Synthesis, radiolabeling and in vivo evaluation of [¹¹C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor', European Journal of Medicinal Chemistry, vol. 79, pp. 152-163. https://doi.org/10.1016/j.ejmech.2014.03.066

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title = "Synthesis, radiolabeling and in vivo evaluation of [11C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor",

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 = "Animals, Brain, CHO Cells, Carbon Isotopes, Cricetulus, HEK293 Cells, Humans, Kinetics, Ligands, Molecular Structure, Phenols, Piperazines, Positron-Emission Tomography, Propanols, Pyrazines, Radiopharmaceuticals, Receptors, Serotonin, Sulfonamides, Swine, Tissue Distribution",

author = "Hansen, {Hanne Demant} and Enza Lacivita and {Di Pilato}, Pantaleo and Herth, {Matthias M} and Szabolcs Lehel and Anders Ettrup and Andersen, {Valdemar L} and Agnete Dyssegaard and {De Giorgio}, Paola and Roberto Perrone and Francesco Berardi and Colabufo, {Nicola Antonio} and Mauro Niso and Knudsen, {Gitte M} and Marcello Leopoldo",

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doi = "10.1016/j.ejmech.2014.03.066",

language = "English",

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journal = "European Journal of Medicinal Chemistry",

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T1 - Synthesis, radiolabeling and in vivo evaluation of [11C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor

AU - Hansen, Hanne Demant

AU - Lacivita, Enza

AU - Di Pilato, Pantaleo

AU - Herth, Matthias M

AU - Lehel, Szabolcs

AU - Ettrup, Anders

AU - Andersen, Valdemar L

AU - Dyssegaard, Agnete

AU - De Giorgio, Paola

AU - Perrone, Roberto

AU - Berardi, Francesco

AU - Colabufo, Nicola Antonio

AU - Niso, Mauro

AU - Knudsen, Gitte M

AU - Leopoldo, Marcello

PY - 2014/5/22

Y1 - 2014/5/22

N2 - 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.

AB - 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.

KW - Animals

KW - Brain

KW - CHO Cells

KW - Carbon Isotopes

KW - Cricetulus

KW - HEK293 Cells

KW - Humans

KW - Kinetics

KW - Ligands

KW - Molecular Structure

KW - Phenols

KW - Piperazines

KW - Positron-Emission Tomography

KW - Propanols

KW - Pyrazines

KW - Radiopharmaceuticals

KW - Receptors, Serotonin

KW - Sulfonamides

KW - Swine

KW - Tissue Distribution

U2 - 10.1016/j.ejmech.2014.03.066

DO - 10.1016/j.ejmech.2014.03.066

M3 - Journal article

C2 - 24732791

SN - 0223-5234

VL - 79

SP - 152

EP - 163

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry