Bruton's tyrosine kinase (BTK) is a key component in the B-cell receptor signaling pathway, and is consequently a target for in vivo imaging of B-cell malignancies as well as in multiple sclerosis (MS) with positron emission tomography (PET). A recent Phase 2b study with Sanofi's BTK inhibitor, Tolebrutinib (a.k.a. SAR442168, PRN2246 or BTK'168) showed significantly reduced disease activity associated with MS. Herein, we report the radiosynthesis of [11 C]Tolebrutinib ([11 C]5) as a potential PET imaging agent for BTK. The N-[11 C]acrylamide moiety of [11 C]5 was labelled by 11 C-carbonylation starting from [11 C]CO, iodoethylene, and the secondary amine precursor via a novel Palladium-NiXantphos-mediated carbonylation protocol, and the synthesis was fully automated using a commercial carbon-11 synthesis platform (TracerMakerTM , Scansys Laboratorieteknik). [11 C]5 was obtained in a decay-corrected radiochemical yield of 37 ± 2% (n = 5, relative to starting [11 C]CO activity) in >99% radiochemical purity, with an average molar activity of 45 GBq/μmol (1200 mCi/μmol). We envision that this methodology will be generally applicable for the syntheses of labeled N-acrylamides.

中文翻译：

---

Bruton 酪氨酸激酶抑制剂 [11 C] Tolebrutinib 通过钯-NiXantphos 介导的羰基化的放射合成

布鲁顿酪氨酸激酶 (BTK) 是 B 细胞受体信号通路中的关键成分，因此是 B 细胞恶性肿瘤以及多发性硬化症 (MS) 与正电子发射断层扫描 (PET) 体内成像的目标。最近使用赛诺菲的 BTK 抑制剂 Tolebrutinib（又名 SAR442168、PRN2246 或 BTK'168）进行的 2b 期研究显示，与 MS 相关的疾病活动性显着降低。在此，我们报告了 [11 C] 托布替尼 ([11 C]5) 的放射合成作为 BTK 的潜在 PET 显像剂。[11 C]5 的 N-[11 C]丙烯酰胺部分被 11 C-羰基化标记，从 [11 C]CO、碘乙烯和仲胺前体开始，通过一种新型的钯-NiXantphos 介导的羰基化方案，以及使用商业碳 11 合成平台（TracerMakerTM，Scansys 实验室）。[11 C]5 以 37 ± 2%（n = 5，相对于起始 [11 C]CO 活性）的衰减校正放射化学产率获得，放射化学纯度大于 99%，平均摩尔活性为 45 GBq/ μmol (1200 mCi/μmol)。我们设想这种方法将普遍适用于标记 N-丙烯酰胺的合成。