Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton's Tyrosine Kinase.
Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton's Tyrosine Kinase.
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DOI：
10.1021/acsptsci.2c00215
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发表时间：
2023-02
影响因子：
6
通讯作者：
Kaixuan Li;Mingqian Wang;Melike Akoglu;Alyssa C. Pollard;J. Klecker;P. Alfonso;Ana Corrionero;Niall Prendiville;Wenchao Qu;Matthew F. L. Parker;N. Turkman;Jules A. Cohen;P. Tonge
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文献类型：
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作者：
Kaixuan Li;Mingqian Wang;Melike Akoglu;Alyssa C. Pollard;J. Klecker;P. Alfonso;Ana Corrionero;Niall Prendiville;Wenchao Qu;Matthew F. L. Parker;N. Turkman;Jules A. Cohen;P. Tonge
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标。为了帮助发现和开发BTK抑制剂并改善临床诊断，我们开发了基于选择性BTK抑制剂雷米替尼的正电子发射断层扫描（PET）放射性示踪剂。[18 F] PTBTK 3是一种芳香族18 F标记示踪剂，分3步合成，衰变校正放射化学产率为14.8 ± 2.4%，放射化学纯度≥99%。使用雷米替尼或非放射性PTBTK 3，JeKo-1细胞中[18 F] PTBTK 3的细胞摄取被阻断高达97%。[18 F] PTBTK 3在NOD SCID（非肥胖糖尿病/重度联合免疫缺陷）小鼠中显示出肾脏和肝胆清除率，注射后60 min时，BTK阳性JeKo-1异种移植物中[18 F] PTBTK 3的肿瘤摄取（1.23 ± 0.30% ID/cc）显著高于BTK阴性U87 MG异种移植物中的肿瘤摄取（0.41 ± 0.11% ID/cc）。在JeKo-1异种移植物中，肿瘤摄取被雷米替尼阻断高达62%，表明肿瘤中[18 F] PTBTK 3的BTK依赖性摄取。
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. [18F]PTBTK3 is an aromatic, 18F-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 [18F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/severe combined immunodeficiency) mice, and the tumor uptake of [18F]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 [18F]PTBTK3 in tumors.