MER tyrosine kinase (MERTK) upregulation is associated with M2 polarization of microglia, which plays a vital role in neuroregeneration following damage induced by neuroinflammatory diseases such as multiple sclerosis (MS). Therefore, a radiotracer specific for MERTK could be of great utility in the clinical management of MS, for the detection and differentiation of neuroregenerative and neurodegenerative processes. This study aimed to develop an [¹⁸F] ligand with high affinity and selectivity for MERTK as a potential positron emission tomography (PET) radiotracer. MIPS15691 and MIPS15692 were synthesized and kinase assays were utilized to determine potency and selectivity for MERTK. Both compounds were shown to be potent against MERTK, with respective IC₅₀ values of 4.6 nM and 4.0 nM, and were also MERTK-selective. Plasma and brain pharmacokinetics were measured in mice and led to selection of MIPS15692 over MIPS15691. X-ray crystallography was used to visualize how MIPS15692 is recognized by the enzyme. [¹⁸F]MIPS15692 was synthesized using an automated iPHASE FlexLab module, with a molar activity (A_m) of 49 ± 26 GBq/μmol. The radiochemical purity of [¹⁸F]MIPS15692 was >99% and the decay-corrected radiochemical yields (RCYs) were determined as 2.45 ± 0.85%. Brain MERTK protein density was measured by a saturation binding assay in the brain slices of a cuprizone mouse model of MS. High levels of specific binding of [¹⁸F]MIPS15692 to MERTK were found, especially in the corpus callosum/hippocampus (CC/HC). The in vivo PET imaging study of [¹⁸F]MIPS15692 suggested that its neuroPK is sub-optimal for clinical use. Current efforts are underway to optimize the neuroPK of our next generation PET radiotracers for maximal in vivo utility.

MER 酪氨酸激酶 (MERTK) 上调与小胶质细胞的 M2 极化有关，小胶质细胞在多发性硬化症 (MS) 等神经炎性疾病引起的损伤后的神经再生中起着至关重要的作用。因此，一种针对 MERTK 的放射性示踪剂可能在 MS 的临床管理中非常有用，用于检测和区分神经再生和神经退行性过程。本研究旨在开发一种对 MERTK 具有高亲和力和选择性的 [ ¹⁸ F] 配体，作为潜在的正电子发射断层扫描 (PET) 放射性示踪剂。合成了 MIPS15691 和 MIPS15692，并利用激酶测定来确定 MERTK 的效力和选择性。两种化合物均显示对 MERTK 有效，IC 为₅₀4.6 nM 和 4.0 nM 的值，并且也是 MERTK 选择性的。在小鼠中测量血浆和脑药代动力学并导致选择 MIPS15692 而不是 MIPS15691。X 射线晶体学用于可视化 MIPS15692 如何被酶识别。[ ¹⁸ F]MIPS15692 使用自动化 iPHASE FlexLab 模块合成，摩尔活性 (A _m ) 为 49 ± 26 GBq/μmol。[ ¹⁸ F]MIPS15692 的放射化学纯度 > 99%，衰减校正放射化学产率 (RCY) 确定为 2.45 ± 0.85%。脑 MERTK 蛋白密度通过饱和结合试验在铜宗 MS 小鼠模型的脑切片中测量。^{[ 18}的高水平特异性结合F]MIPS15692 对 MERTK 被发现，特别是在胼胝体/海马体 (CC/HC)。^{[ 18} F]MIPS15692的体内PET成像研究表明，其neuroPK对于临床使用而言不是最佳的。目前正在努力优化我们下一代 PET 放射性示踪剂的神经PK，以实现最大的体内效用。