18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain

Liang Wang; Jiajun Ye; Yingfang He; Winnie Deuther-Conrad; Jinming Zhang; Xiaojun Zhang; Mengchao Cui; Jörg Steinbach; Yiyun Huang; Peter Brust; Hongmei Jia

doi:10.1016/j.bmc.2017.05.019

¹⁸F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain

Bioorg Med Chem. 2017 Jul 15;25(14):3792-3802. doi: 10.1016/j.bmc.2017.05.019. Epub 2017 May 10.

Authors

Affiliations

¹ Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
² Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany.
³ Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China.
⁴ Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China. Electronic address: cmc@bnu.edu.cn.
⁵ PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
⁶ Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China. Electronic address: hmjia@bnu.edu.cn.

PMID: 28549890
DOI: 10.1016/j.bmc.2017.05.019

Abstract

We have designed and synthesized a series of indole-based σ₂ receptor ligands containing 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as pharmacophore. In vitro competition binding assays showed that all ten ligands possessed low nanomolar affinity (K_i=1.79-5.23nM) for σ₂ receptors and high subtype selectivity (K_i (σ₂)/K_i (σ₁)=56-708). Moreover, they showed high selectivity for σ₂ receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [¹⁸F]16 and [¹⁸F]21 were prepared by an efficient one-pot, two-step reaction sequence with a home-made automated synthesis module, with 10-15% radiochemical yield and radiochemical purity of >99%. Both radiotracers showed high brain uptake and σ₂ receptor binding specificity in mice.

Keywords: (18)F; Brain; Indole-based analogs; Sigma-2 receptors.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Animals
Binding, Competitive / drug effects
Brain / metabolism*
Chromatography, High Pressure Liquid
Fluorine Radioisotopes / chemistry
Half-Life
Indoles / analysis
Indoles / chemistry*
Indoles / pharmacokinetics
Indoles / pharmacology
Ligands
Male
Mice
Mice, Inbred ICR
Protein Binding
Radiopharmaceuticals / analysis
Radiopharmaceuticals / chemistry*
Radiopharmaceuticals / pharmacokinetics
Radiopharmaceuticals / pharmacology
Receptors, sigma / chemistry
Receptors, sigma / metabolism*
Structure-Activity Relationship
Tissue Distribution
Vesicular Acetylcholine Transport Proteins / chemistry
Vesicular Acetylcholine Transport Proteins / metabolism

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Fluorine Radioisotopes
Indoles
Ligands
Radiopharmaceuticals
Receptors, sigma
Vesicular Acetylcholine Transport Proteins
sigma-2 receptor