Synthesis and preliminary biological evaluation of [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate for the fractalkine receptor (CX3CR1)

Mingzhang Gao; Min Wang; Jill A Meyer; Jonathan S Peters; Hamideh Zarrinmayeh; Paul R Territo; Gary D Hutchins; Qi-Huang Zheng

doi:10.1016/j.bmcl.2017.04.052

Synthesis and preliminary biological evaluation of [¹¹C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate for the fractalkine receptor (CX₃CR1)

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2727-2730. doi: 10.1016/j.bmcl.2017.04.052. Epub 2017 Apr 24.

Authors

Mingzhang Gao¹, Min Wang¹, Jill A Meyer¹, Jonathan S Peters¹, Hamideh Zarrinmayeh¹, Paul R Territo¹, Gary D Hutchins¹, Qi-Huang Zheng²

Affiliations

¹ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, Room 202, Indianapolis, IN 46202, USA.
² Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, Room 202, Indianapolis, IN 46202, USA. Electronic address: qzheng@iupui.edu.

PMID: 28462835
DOI: 10.1016/j.bmcl.2017.04.052

Abstract

The reference standard methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate (5) and its precursor 2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucine (6) were synthesized from 6-amino-2-mercaptopyrimidin-4-ol and BnBr with overall chemical yield 7% in five steps and 4% in six steps, respectively. The target tracer [¹¹C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate ([¹¹C]5) was prepared from the acid precursor with [¹¹C]CH₃OTf through O-[¹¹C]methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370-1110GBq/μmol with a total synthesis time of ∼40-min from EOB. The radioligand depletion experiment of [¹¹C]5 did not display specific binding to CX₃CR1, and the competitive binding assay of ligand 5 found much lower CX₃CR1 binding affinity.

Keywords: Competitive binding assay; Fractalkine receptor (CX(3)CR1); Positron emission tomography (PET); Radioligand depletion experiment; Radiosynthesis; [(11)C]Methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate.

Publication types

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

MeSH terms

CX3C Chemokine Receptor 1
Carbon Isotopes
Dose-Response Relationship, Drug
Humans
Leucine / analogs & derivatives*
Leucine / chemical synthesis
Leucine / chemistry
Leucine / pharmacology
Ligands
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptors, Chemokine / antagonists & inhibitors*
Receptors, Chemokine / metabolism
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

CX3C Chemokine Receptor 1
CX3CR1 protein, human
Carbon Isotopes
Ligands
Pyrimidines
Receptors, Chemokine
Thiazoles
Leucine