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Published on: February 17, 2022
Novel technetium-99m-labelled ribociclib isocyanide derivatives for imaging cyclin-dependent kinase 4/6 (CDK4/6)
Peiwen Han1, Yuhao Jiang1, Qing Ruan2
1Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Abstract:
Cyclin-dependent kinase 4/6 (CDK4/6) plays a crucial role in cell cycle regulation, is overexpressed in various cancers and is an important target in the development of radiotracers for tumour imaging. Despite the increasing recognition of CDK4/6 inhibitors in cancer therapy, their application is limited by the lack of suitable biomarkers. Herein, we developed a series of technetium-99m-labelled CDK4/6 radiotracers and utilized a linker optimization strategy to reduce their abdominal uptake and enhance their imaging properties. By introducing polyethylene glycol chains (PEGn, n = 2, 3, or 4) of different lengths, we successfully prepared the first technetium-99m-labelled ribociclib isocyanide derivatives via a one-step method. After rapid screening, we selected [99mTc]Tc-RIB-PEG4-CN (LogD7.4 = 0.01 ± 0.01) because of its superior uptake in the cell lines and suitable nontarget uptake in vivo. Additionally, it displayed nanomolar affinity (5.887 ± 0.3579 nM). In HCT116 xenograft models, the probe exhibited significant tumour uptake (2.44 ± 0.29 % ID/g at 4 h p.i.) while maintaining reduced abdominal uptake. Moreover, the probe showed specificity in HCT116 xenograft models, as evidenced by a 49.2 % decrease in the tumour-to-muscle ratio in the presence of excess ribociclib for blocking. Micro-SPECT/CT images of HCT116 and MCF-7 xenografts revealed the liver metabolism of [99mTc]Tc-RIB-PEG4-CN, with robust tumour retention and comparatively low abdominal uptake at 4 h p.i. This novel radiotracer enables the noninvasive evaluation of CDK4/6 expression, providing valuable insights for clinical treatment strategies and further mechanistic studies.
Insights
Researchers developed a new technetium-99m radiotracer for imaging cyclin-dependent kinase 4/6 (CDK4/6) expression. This novel probe shows promise for non-invasively assessing CDK4/6 in tumors, aiding cancer therapy decisions.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiochemistry
Background:
- Cyclin-dependent kinase 4/6 (CDK4/6) is crucial for cell cycle regulation and frequently overexpressed in cancers.
- CDK4/6 inhibitors are vital cancer therapies, but lack suitable imaging biomarkers.
- Accurate assessment of CDK4/6 expression is needed for effective cancer treatment strategies.
Purpose of the Study:
- To develop and evaluate novel technetium-99m-labeled radiotracers for non-invasive imaging of CDK4/6 expression.
- To optimize radiotracer properties, specifically reducing abdominal uptake and enhancing tumor visualization.
- To assess the diagnostic potential of the lead radiotracer in preclinical cancer models.
Main Methods:
- Synthesis of technetium-99m-labeled ribociclib isocyanide derivatives with varying polyethylene glycol (PEG) chain lengths.
- Screening and selection of the optimal radiotracer ([99mTc]Tc-RIB-PEG4-CN) based on cell uptake and in vivo biodistribution.
- Evaluation of tumor uptake, non-target organ uptake, specificity (blocking studies), and imaging performance in HCT116 and MCF-7 xenograft models using micro-SPECT/CT.
Main Results:
- A series of [99mTc]-labeled ribociclib derivatives were successfully synthesized using a one-step method.
- [99mTc]Tc-RIB-PEG4-CN demonstrated superior cell uptake, nanomolar affinity, and favorable biodistribution with reduced abdominal uptake.
- Significant tumor uptake (2.44 ± 0.29 % ID/g at 4 h p.i.) and high tumor-to-muscle ratio were observed in HCT116 xenografts.
- Micro-SPECT/CT imaging confirmed robust tumor retention and low non-target uptake, with evidence of liver metabolism.
Conclusions:
- [99mTc]Tc-RIB-PEG4-CN is the first technetium-99m-labeled ribociclib derivative developed for CDK4/6 imaging.
- The optimized radiotracer exhibits excellent properties for non-invasive assessment of CDK4/6 expression in tumors.
- This novel probe holds significant potential for guiding clinical treatment strategies and advancing mechanistic studies in oncology.
