Development of a radioligand for imaging V1a vasopressin receptors with PET

Ravi Naik; Heather Valentine; Andrew Hall; William B. Mathews; James C. Harris; C. Sue Carter; Robert F. Dannals; Dean F. Wong; Andrew G. Horti

doi:10.1016/j.ejmech.2017.08.037

Development of a radioligand for imaging V_1a vasopressin receptors with PET

Ravi Naik, Heather Valentine, Andrew Hall, William B. Mathews, James C. Harris, C. Sue Carter, Robert F. Dannals, Dean F. Wong, Andrew G. Horti

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

A series of vasopressin receptor V_1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3-yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with ¹¹C for PET studies. [¹¹CH₃](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30–34%) labeled V_1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [¹¹CH₃](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V_1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V_1a receptor.

Original language	English (US)
Pages (from-to)	644-656
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	139
DOIs	https://doi.org/10.1016/j.ejmech.2017.08.037
State	Published - Oct 20 2017

Keywords

Positron emission tomography
Radiotracers
Vasopressin receptor

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

Access to Document

10.1016/j.ejmech.2017.08.037

Cite this

@article{f78567667c1c40caa61fe933e80a26df,

title = "Development of a radioligand for imaging V1a vasopressin receptors with PET",

abstract = "A series of vasopressin receptor V1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3-yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with 11C for PET studies. [11CH3](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30–34%) labeled V1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [11CH3](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V1a receptor.",

keywords = "Positron emission tomography, Radiotracers, Vasopressin receptor",

author = "Ravi Naik and Heather Valentine and Andrew Hall and Mathews, {William B.} and Harris, {James C.} and Carter, {C. Sue} and Dannals, {Robert F.} and Wong, {Dean F.} and Horti, {Andrew G.}",

note = "Funding Information: This research was supported in part by NIH grant R01MH107197 (Wong, Horti), John Davis Foundation grant and Division of Nuclear Medicine and Molecular Imaging . We thank Paige Finley and Polina Sysa Shah for the help with animal experiments and Julia Buchanan for editorial comments. Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = oct,

day = "20",

doi = "10.1016/j.ejmech.2017.08.037",

language = "English (US)",

volume = "139",

pages = "644--656",

journal = "CHIM.THER.",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Development of a radioligand for imaging V1a vasopressin receptors with PET

AU - Naik, Ravi

AU - Valentine, Heather

AU - Hall, Andrew

AU - Mathews, William B.

AU - Harris, James C.

AU - Carter, C. Sue

AU - Dannals, Robert F.

AU - Wong, Dean F.

AU - Horti, Andrew G.

N1 - Funding Information: This research was supported in part by NIH grant R01MH107197 (Wong, Horti), John Davis Foundation grant and Division of Nuclear Medicine and Molecular Imaging . We thank Paige Finley and Polina Sysa Shah for the help with animal experiments and Julia Buchanan for editorial comments. Publisher Copyright: © 2017

PY - 2017/10/20

Y1 - 2017/10/20

N2 - A series of vasopressin receptor V1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3-yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with 11C for PET studies. [11CH3](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30–34%) labeled V1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [11CH3](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V1a receptor.

AB - A series of vasopressin receptor V1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3-yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with 11C for PET studies. [11CH3](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30–34%) labeled V1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [11CH3](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V1a receptor.

KW - Positron emission tomography

KW - Radiotracers

KW - Vasopressin receptor

UR - http://www.scopus.com/inward/record.url?scp=85027991825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027991825&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2017.08.037

DO - 10.1016/j.ejmech.2017.08.037

M3 - Article

C2 - 28843869

AN - SCOPUS:85027991825

VL - 139

SP - 644

EP - 656

JO - CHIM.THER.

JF - CHIM.THER.

SN - 0223-5234

ER -