Noninvasive PET Imaging of CDK4/6 Activation in Breast Cancer
| Autor: | Giuseppe Carlucci, Youssef Zaim Wadghiri, Zakia Ben Youss Gironda, Nicholas Ramos, Jairo Baquero-Buitrago, Fernando E. Boada, Thomas Reiner |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Biodistribution Fluorine Radioisotopes Breast Neoplasms Palbociclib Pharmacology 03 medical and health sciences Mice 0302 clinical medicine Breast cancer In vivo medicine Animals Humans Radiology Nuclear Medicine and imaging Tissue Distribution Protein Kinase Inhibitors Radiochemistry biology Chemistry Cyclin-Dependent Kinase 4 Biological Transport Cyclin-Dependent Kinase 6 medicine.disease Imaging agent Enzyme Activation 030104 developmental biology MCF-7 030220 oncology & carcinogenesis Isotope Labeling Positron-Emission Tomography biology.protein MCF-7 Cells Female Cyclin-dependent kinase 6 Preclinical imaging Half-Life |
| Zdroj: | J Nucl Med |
| Popis: | The cell cycle is a progression of four distinct phases (G1, S, G2, M), with various cycle proteins being essential in regulating this process. In breast cancer, alterations in the cell cycle and uncontrolled proliferation led to several studies interrogating the relationship between cyclins and their counterpart cyclin-dependent-kinases (CDKs). We aimed to develop a radiolabeled 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 ER-positive HER2-negative breast cancer. Methods: [18F]-CDKi was synthesized and assayed for its inhibitory activities 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 activity and specificity was assessed in a MCF-7 cell line and in mice bearing MCF-7 breast tumors. Non radioactive Palbociclib (Inbrance, Pfizer®) was used as blocking agent to investigate the binding specificity and selectivity of [18F]-CDKi. Results: To generate [18F]-CDKi, we introduced an F-18 prosthetic group (18F-fluorobenzoic acid, [18F-FBA]), and transformed palbociclib into a different, PET active functional molecule. [18F]-CDKi was obtained with an overall radiochemical uncorrected yield of 15% and radiochemical purity > 98 %. The total synthesis time from the start of synthesis to final injectable formulated tracer is 70 minutes. The retention time reported for [18F]-CDKi and [19F]-CDKi is 27.4 min as demonstrated by co-injection with [19F]-CDKi in a HPLC. The first experiments aimed to analyze pharmacokinetics (PK) and in vitro activity of [18F]-CDKi (figure 5, Blood HL). In vivo blood half-life [t1/2(weighted) = 7.03 minutes], and octanol/water phase partition coefficient (logDO/W = 1.91 ± 0.24) showed a mainly lipophilic behavior. [18F]-CDKi is stable in vitro and in vivo (>98% at 4h post injection) and maintained its potent targeting affinity to CDK4/6 (~13NM for CDK4 and ~15nM for CDK6). Cellular uptake experiments performed in MCF-7 breast cancer cell line (ER-positive/HER2-negative) demonstrated specific uptake with a maximum intracellular concentration of ~65% as early as 10 minutes post incubation. The tracer uptake was reduced to |
| Databáze: | OpenAIRE |
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