Noninvasive PET imaging of CDK4/6 activation in breast cancer Journal Article


Authors: Ramos, N.; Baquero-Buitrago, J.; Ben Youss Gironda, Z.; Wadghiri, Y. Z.; Reiner, T.; Boada, F. E.; Carlucci, G.
Article Title: Noninvasive PET imaging of CDK4/6 activation in breast cancer
Abstract: The cell cycle is a progression of 4 distinct phases (G1, S, G2, and M), with various cycle proteins being essential in regulating this process. We aimed to develop a radiolabeled cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for breast cancer imaging. Our transfluorinated analog (18F-CDKi) was evaluated and validated as a novel PET imaging agent to quantify CDK4/6 expression in estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods:18F-CDKi was synthesized and assayed against CDK4/6 kinases. 18F-CDKi was prepared with a 2-step automated synthetic strategy that yielded the final product with remarkable purity and molar activity. In vitro and in vivo biologic specificity was assessed in a MCF-7 cell line and in mice bearing MCF-7 breast tumors. Nonradioactive palbociclib was used as a blocking agent to investigate the binding specificity and selectivity of 18F-CDKi. Results:18F-CDKi was obtained with an overall radiochemical uncorrected yield of 15% and radiochemical purity higher than 98%. The total time from the start of synthesis to the final injectable formulated tracer is 70 min. The retention time reported for 18F-CDKi and 19F-CDKi is 27.4 min as demonstrated by coinjection with 19F-CDKi in a high-pressure liquid chromatograph. In vivo blood half-life (weighted, 7.03 min) and octanol/water phase partition coefficient (1.91 ± 0.24) showed a mainly lipophilic behavior. 18F-CDKi is stable in vitro and in vivo (>98% at 4 h after injection) and maintained its potent targeting affinity to CDK4/6. Cellular uptake experiments performed on the MCF-7 breast cancer cell line (ER-positive and HER2-negative) demonstrated specific uptake with a maximum intracellular concentration of about 65% as early as 10 min after incubation. The tracer uptake was reduced to less than 5% when cells were coincubated with a molar excess of palbociclib. In vivo imaging and ex vivo biodistribution of ER-positive, HER2-negative MCF-7 breast cancer models showed a specific uptake of approximately 4% injected dose/g of tumor (reduced to ∼0.3% with a 50-fold excess of cold palbociclib). A comprehensive biodistribution analysis also revealed a significantly lower activation of CDK4/6 in nontargeting organs. Conclusion:18F-CDKi represents the first 18F PET CDK4/6 imaging agent and a promising imaging agent for ER-positive, HER2-negative breast cancer. © 2020 by the Society of Nuclear Medicine and Molecular Imaging.
Keywords: cell cycle; breast cancer; pet/ct imaging; mcf-7; cdk4/6
Journal Title: Journal of Nuclear Medicine
Volume: 61
Issue: 3
ISSN: 0161-5505
Publisher: Society of Nuclear Medicine  
Date Published: 2020-03-01
Start Page: 437
End Page: 442
Language: English
DOI: 10.2967/jnumed.119.232603
PUBMED: 31481582
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 April 2020 -- Source: Scopus
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  1. Thomas Reiner
    99 Reiner