Radiosynthesis of [11C]Ibrutinib via Pd-Mediated [11C]CO Carbonylation: Preliminary PET Imaging in Experimental Autoimmune Encephalomyelitis Mice

Junchao Tong,Amanda J Boyle,Dongxu Zhai,Michael B Harkness,David J Donnelly,Tritin Tran,Armando Garcia,Fang Liu,Neil Vasdev,Anton Lindberg

doi:10.3389/fnume.2021.772289

Abstract

Ibrutinib is a first-generation Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in autoimmune diseases and has consequently been developed as a positron emission tomography (PET) radiotracer. Herein, we report the automated radiosynthesis of [11C]ibrutinib through 11C-carbonylation of the acrylamide functional group, by reaction of the secondary amine precursor with [11C]CO, iodoethylene, and palladium–NiXantphos. [11C]Ibrutinib was reliably formulated in radiochemical yields of 5.4% ± 2.5% (non-decay corrected; n = 9, relative to starting [11C]CO2), radiochemical purity &gt;99%, and molar activity of 58.8 ± 30.8 GBq/μmol (1.55 ± 0.83 Ci/μmol). Preliminary PET/magnetic resonance imaging with [11C]ibrutinib in experimental autoimmune encephalomyelitis (EAE) mice showed a 49% higher radioactivity accumulation in the spinal cord of mice with EAE scores of 2.5 vs. sham mice.

Highlights

Bruton’s tyrosine kinase (BTK) is critical for the maturation of B cells and in regulating hematopoietic cell circulation [1, 2]
The N-acrylamide moiety of ibrutinib lends this structure well for [11C]CO carbonylation utilizing a new Pd-mediated methodology that we recently reported for the radiolabeling of another BTK inhibitor, [11C]tolebrutinib [15]
Available anhydrous tetrahydrofuran (THF) solvent was used, eliminating the need for freshly distilled THF, and the semi-preparative high-performance liquid chromatography (HPLC) employed a flow rate of 6.0 ml/min. [11C]Ibrutinib was produced in 45–50 min overall synthesis time from end of bombardment (EOB) with a retention time of 12–13 min (Figure 2A). [11C]Ibrutinib was synthesized in 5.4 ± 2.5% (n = 9) RCY relative to [11C]CO2, with RCP >99%, as confirmed by co-injection of authentic standard (Figure 2B), and Am of 58.8 ± 30.8 GBq/μmol (1.55 ± 0.83 Ci/μmol) as measured by HPLC

Summary

Introduction

Bruton’s tyrosine kinase (BTK) is critical for the maturation of B cells and in regulating hematopoietic cell circulation [1, 2]. BTK inhibitors have been developed to treat B-cell malignancies and autoimmune diseases including multiple sclerosis (MS) [3, 4], where it is postulated that inhibiting BTK blocks the maturation of B cells [5,6,7,8,9]. Ibrutinib is a first-generation BTK inhibitor used as a chemotherapeutic agent to treat B-cell cancers [10]. Ibrutinib has not been studied clinically as a BTK inhibitor in MS, it has shown efficacy in other autoimmune diseases, such as arthritis, lupus, and recently in treatment of COVID-19 (SARS-CoV-2) [11,12,13,14]. The versatility of BTK inhibitors, such as ibrutinib, in treating various B-cell-related diseases has led to their development as radiotracers for positron emission tomography (PET) [15, 16]. The method resulted in low radiochemical yields (RCYs)

Methods

Results

Conclusion