Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) receptors

Jeffrey S Stehouwer; Chase H Bourke; Michael J Owens; Ronald J Voll; Clinton D Kilts; Mark M Goodman

doi:10.1016/j.bmcl.2015.10.010

Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) receptors

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5111-4. doi: 10.1016/j.bmcl.2015.10.010. Epub 2015 Oct 8.

Authors

Jeffrey S Stehouwer¹, Chase H Bourke², Michael J Owens², Ronald J Voll³, Clinton D Kilts⁴, Mark M Goodman⁵

Affiliations

¹ Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA. Electronic address: jstehou@emory.edu.
² Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
³ Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA.
⁴ Psychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
⁵ Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.

Abstract

Compounds 1-14 were synthesized in a search for high-affinity CRF1 receptor ligands that could be radiolabeled with (11)C or (18)F for use as positron emission tomography (PET) radiotracers. Derivatives of 2 were developed which contained amide N-fluoroalkyl substituents. Compounds [(18)F]24 and [(18)F]25 were found to have appropriate lipophilicities of logP7.4=2.2 but microPET imaging with [(18)F]25 demonstrated limited brain uptake.

Keywords: CRF-1 receptor; Corticotropin-releasing factor; Fluorine-18; PET imaging; Positron emission tomography.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aminopyridines / chemical synthesis
Aminopyridines / metabolism
Aminopyridines / pharmacology*
Animals
Brain / metabolism*
Cell Line
Fluorine Radioisotopes
Heterocyclic Compounds, 2-Ring / chemical synthesis
Heterocyclic Compounds, 2-Ring / metabolism
Heterocyclic Compounds, 2-Ring / pharmacology*
Humans
Ligands
Macaca fascicularis
Male
Peptide Fragments / chemistry
Positron-Emission Tomography
Pyrazines / chemical synthesis
Pyrazines / metabolism
Pyrazines / pharmacology*
Radiopharmaceuticals / chemical synthesis
Radiopharmaceuticals / metabolism
Radiopharmaceuticals / pharmacology*
Receptors, Corticotropin-Releasing Hormone / metabolism*

Substances

Aminopyridines
CRF receptor type 2
Fluorine Radioisotopes
Heterocyclic Compounds, 2-Ring
Ligands
Peptide Fragments
Pyrazines
Radiopharmaceuticals
Receptors, Corticotropin-Releasing Hormone
antisauvagine 30
CRF receptor type 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding