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Published on: October 26, 2018
Optimized CDK19 PET Tracers: Spirocyclic-Driven Design and Prostate Cancer Imaging
Jiang Yu1, Zhao Yang2,3, Feifei Xu1
1State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
Abstract:
Cyclin-dependent kinase 19 (CDK19) has been identified as a promising target due to its high expression in prostate cancer (PCa) cells. This study focuses on optimizing the structure of CDK19-targeted imaging tracers. The linker of the lead compound was optimized based on previous structure-activity relationships and cyclization strategy. Incorporating the spirocyclic structure optimized the binding conformation and increased the binding effect of the ligands, which was also reflected in its increased IC50 value. Mice imaging showed clearer tumor lesions and acceptable tissue safety. In addition, 68Ga-IRM-8c identified three distinct lesions in two advanced CRPC patients, located in the pelvis, sacrum, and prostate. The SUVmax values of these lesions were 3.31, 2.93, and 2.73, respectively, with tumor-to-nontumor (T/NT) ratios of 2.30, 2.59, and 2.42. In conclusion, 68Ga-IRM-8c not only effectively detected lesions in PCa patients, but also preliminarily demonstrated tissue safety, further highlighting the potential of CDK19 in PCa diagnosis.
Insights
A novel imaging tracer, 68Ga-IRM-8c, targets Cyclin-dependent kinase 19 (CDK19) for improved prostate cancer (PCa) detection. This tracer successfully identified lesions in advanced PCa patients, showing promising diagnostic potential.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Prostate cancer (PCa) exhibits high expression of Cyclin-dependent kinase 19 (CDK19).
- CDK19 is a potential therapeutic and diagnostic target in PCa.
- Optimizing imaging tracers for CDK19 is crucial for enhanced PCa detection.
Purpose of the Study:
- To optimize the structure of CDK19-targeted imaging tracers for improved PCa detection.
- To evaluate the efficacy and safety of a novel tracer, 68Ga-IRM-8c, in preclinical and clinical settings.
Main Methods:
- Structure-activity relationship studies and cyclization strategies were employed to optimize the lead compound's linker.
- Incorporation of a spirocyclic structure to enhance ligand binding affinity.
- Preclinical imaging in mice and clinical imaging in advanced castration-resistant prostate cancer (CRPC) patients using 68Ga-IRM-8c.
Main Results:
- Spirocyclic structure optimization improved ligand binding conformation and affinity (increased IC50).
- Mice imaging demonstrated clear tumor visualization and acceptable tissue safety.
- 68Ga-IRM-8c successfully identified three distinct lesions in two CRPC patients with favorable tumor-to-nontumor ratios.
Conclusions:
- 68Ga-IRM-8c effectively detects lesions in PCa patients.
- The tracer shows preliminary tissue safety, highlighting CDK19's potential in PCa diagnosis.
- Optimized CDK19-targeted tracers offer a promising avenue for advanced PCa imaging.
