Radiosynthesis and first preclinical evaluation of an 18F-radiolabelled ligand for cancer stem cells by non-invasive PET imaging


Radiosynthesis and first preclinical evaluation of an 18F-radiolabelled ligand for cancer stem cells by non-invasive PET imaging

Toussaint, M.; Moldovan, R.-P.; Teodoro, R.; Gündel, D.; Deuther-Conrad, W.; Brust, P.

Objectives: Cancer stem cells (CSCs) are a multipotent cells subpopulation playing a critical role in tumor initiation, therapy resistance and recurrence1. Therefore, their therapeutic targeting is of relevance for highly aggressive entities with poor prognosis such as glioblastoma (NCT02654964). To support the development of such targeted therapy we intended to develop a radiotracer enabling the non-invasive imaging of the CSCs population. Based on the work of Lucki et al.2 who discovered a promising prodrug termed RIPGBM selective of cancer stem cells (CSC), we aimed at developing an 18F-radiolabelled RIPGBM, and to preliminary assess its potential as non-invasive imaging agent of a low-density population such as the CSC in a mouse model of human glioblastoma. We report in this first exploratory study on the synthesis, radiosynthesis, in vivo metabolism and pharmacokinetics of [18F]RIPGBM.
Methods: The reference compound N-(3-(benzylamino)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-(4-fluorobenzyl)acetamide (RIPGBM) and the corresponding boronic acid pinacol ester precursor for radiofluorination (RM361) were obtained by following the synthetic procedure reported by Lucki and co-workers2. The radiosynthesis of [18F]RIPGBM was performed on an automated module in presence of CU(OTf)2(Py)4, [18F]TBAF and DMA/tBuOH. The fraction of radiometabolites was quantified in mice plasma and brain at 30 min post injection (p.i.). Dynamic PET studies (60 min, nanoScan® PET/MRI, MEDISO, Budapest, Hungary) were performed using an orthotopic xenogenic U87 glioblastoma model in nude mice (n=2) presenting a stem cell-like population3,4.
Results: [18F]RIPGBM was obtained with a radiochemical yield of 6.0 ± 1.3% (EOB), a radiochemical purity >99% and a molar activity of 60-200 GBq/µMol (EOS). It shows a similar stability in both mice at 30 p.i. with 26-30% of intact radiotracer in plasma and 73-74% in the brain. About 70% of intact radiotracer was found in the tumor hemisphere. The PET-derived time-activity curves (TACs) of the whole brain, tumor and contralateral regions displayed a sufficient brain uptake (TAC peak value of 1.0-1.4 SUV). Furthermore, [18F]RIPGBM displays a fast washout from all the above mentioned region.
Conclusion: A fully automated copper-mediated radiosynthetic procedure was developed for the promising prodrug RIPGBM targeting CSCs. A first exploration in vivo demonstrates the presence of 30 % of radiometabolites in the brain/tumor region, no high unspecific retention as shown by the fast washout, but also no observable specific retention in the target area presumably due to the lack of affinity of this radioligand given the low density of the targeted cell population in this model.
References: 1. Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. L. & Rich, J. N. Cancer stem cells in glioblastoma. Genes Dev. 29, 1203–1217 (2015).
2. Lucki, N. C. et al. A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer. PNAS 116, 6435–6440 (2019).
3. Yu, S. et al. Isolation and characterization of cancer stem cells from a human glioblastoma cell line U87. Cancer Letters 265, 124–134 (2008).
4. Toda, Y. et al. DJ-1 Contributes to Self-renewal of Stem Cells in the U87-MG Glioblastoma Cell Line. Anticancer Res 39, 5983–5990 (2019).

Keywords: RIPGBM; 18F-radiolabelled ligand; Positron emission tomography; cancer stem cells

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    International symposium on radiopharmaceutical sciences, 29.05.-02.06.2022, Nantes, France

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