Li Kaixuan, Wang Mingqian, Akoglu Melike, Pollard Alyssa C, Klecker John B, Alfonso Patricia, Corrionero Ana, Prendiville Niall, Qu Wenchao, Parker Matthew F L, Turkman Nashaat, Cohen Jules A, Tonge Peter J
Center for Advanced Study of Drug Action and Department of Chemistry, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
Enzymlogic S.L., QUBE Technology Park, C/Santiago Grisolía, 2, 28760 Madrid, Spain.
ACS Pharmacol Transl Sci. 2023 Feb 10;6(3):410-421. doi: 10.1021/acsptsci.2c00215. eCollection 2023 Mar 10.
Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clinical diagnoses, we have developed a positron emission tomography (PET) radiotracer based on a selective BTK inhibitor, remibrutinib. [F]PTBTK3 is an aromatic, F-labeled tracer that was synthesized in 3 steps with a 14.8 ± 2.4% decay-corrected radiochemical yield and ≥99% radiochemical purity. The cellular uptake of [F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/severe combined immunodeficiency) mice, and the tumor uptake of [F]PTBTK3 in BTK-positive JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-negative U87MG xenografts (0.41 ± 0.11% ID/cc). In the JeKo-1 xenografts, tumor uptake was blocked up to 62% by remibrutinib, indicating the BTK-dependent uptake of [F]PTBTK3 in tumors.
布鲁顿酪氨酸激酶（BTK）是治疗B细胞恶性肿瘤和自身免疫性疾病的靶点。为了助力BTK抑制剂的发现与开发并改善临床诊断，我们基于选择性BTK抑制剂瑞米芦替尼开发了一种正电子发射断层扫描（PET）放射性示踪剂。[F]PTBTK3是一种芳香族、F标记的示踪剂，通过三步合成，衰变校正后的放射化学产率为14.8±2.4%，放射化学纯度≥99%。使用瑞米芦替尼或非放射性PTBTK3时，JeKo-1细胞中[F]PTBTK3的细胞摄取被阻断高达97%。[F]PTBTK3在非肥胖糖尿病/严重联合免疫缺陷（NOD SCID）小鼠中表现出肾和肝胆清除，与BTK阴性的U87MG异种移植瘤（0.41±0.11%ID/cc）中的肿瘤摄取相比，BTK阳性的JeKo-1异种移植瘤在注射后60分钟时[F]PTBTK3的肿瘤摄取（1.23±0.30%ID/cc）显著更高。在JeKo-1异种移植瘤中，瑞米芦替尼将肿瘤摄取阻断高达62%，表明[F]PTBTK3在肿瘤中的摄取依赖于BTK。
