Imaging CDK4/6 Broaden Options of Breast Cancer Diagnostics with Positron Emission Tomography

This study developed a novel PET radiotracer to screen
breast cancer
patients sensitive to CDK4/6 inhibitors, guiding personalized treatment.
Two CDK4/6-targeting precursors were synthesized and evaluated in vitro and in vivo. Three breast cancer
cell linesMCF-7, MDA-MB-231, and MDA-MB-468were selected
based on decreasing sensitivity to palbociclib. Compared to [68Ga]Ga-DOTA-Hexa-CDKi, [68Ga]Ga-DOTA-Bua-CDKi clearly
identified cell lines with high sensitivity to palbociclib. PET/CT
imaging showed significantly higher uptake of [68Ga]Ga-DOTA-Bua-CDKi
(8.40 ± 0.85%ID/g) in MCF-7 tumors 60 min after tracer injection,
with significant differences in tumor uptake among the three models
(P < 0.05). Blocking assays demonstrated specific
tumor uptake of [68Ga]Ga-DOTA-Bua-CDKi. Biosafety tests
validated its safety as a diagnostic agent. [68Ga]Ga-DOTA-Bua-CDKi
showed highly specific targeting of CDK4/6 and effective contrast
imaging in tumor models. To our knowledge, [68Ga]Ga-DOTA-Bua-CDKi
is one of the first radiotracers to assess CDK inhibitor sensitivity,
offering promise for evaluating patient responses to CDK4/6 inhibitors.

本研究开发了一种新型正电子发射断层扫描（Positron Emission Tomography, PET）放射性示踪剂，用于筛选对细胞周期蛋白依赖性激酶4/6（Cyclin-dependent kinase 4/6, CDK4/6）抑制剂敏感的乳腺癌患者，以指导个体化治疗。本研究合成了两种靶向CDK4/6的前体化合物，并开展了体外与体内评价。选取了三种乳腺癌细胞系——MCF-7、MDA-MB-231及MDA-MB-468，其对帕博西尼（palbociclib）的敏感性依次递减。与[68Ga]Ga-DOTA-Hexa-CDKi相比，[68Ga]Ga-DOTA-Bua-CDKi可清晰区分对帕博西尼具有高敏感性的细胞系。PET/CT成像结果显示，在示踪剂注射后60分钟，MCF-7肿瘤组织中[68Ga]Ga-DOTA-Bua-CDKi的摄取量显著更高（8.40 ± 0.85%ID/g），且三种肿瘤模型的肿瘤摄取量存在显著统计学差异（P < 0.05）。阻断实验证实了[68Ga]Ga-DOTA-Bua-CDKi的肿瘤摄取具有特异性。生物安全性实验验证了其作为诊断制剂的安全性。[68Ga]Ga-DOTA-Bua-CDKi可实现对CDK4/6的高特异性靶向，并在肿瘤模型中实现有效的对比成像。据我们所知，[68Ga]Ga-DOTA-Bua-CDKi是首批可评估CDK抑制剂敏感性的放射性示踪剂之一，为评估患者对CDK4/6抑制剂的治疗应答提供了应用前景。