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PET and MRI Guided Irradiation of a Glioblastoma Rat Model Using a Micro-irradiator
Published on: December 28, 2017
Radioiodinated compound FJR01: a novel P2X7R-targeted SPECT tracer for visualizing glioma-associated
Xiyan Rui1,2, Shengxuan Sun1,2, Yuzhou Ding1,3
1School of Pharmaceutical Sciences and Minhang Hospital, Fudan University, Shanghai, China.
Abstract:
The P2X7 receptor (P2X7R) is an imaging biomarker of glioblastoma-associated microglia/macrophages (GAMMs), yet no SPECT tracer is currently available for GAMM imaging. Guided by the high-affinity P2X7R scaffold JNJ-64413739 and molecular docking, we designed two radioiodination-ready analogues, FJR01 and FJR02. Compounds were screened in vitro using homogenates from cell lines stably expressing mouse or human P2X7R; FJR01 was prioritised (hP2X7R, IC50 = 8.8 nM). Radioiodination afforded [131I]FJR01 in high radiochemical yield (95%) with excellent stability. In normal mice, biodistribution showed high brain uptake and rapid clearance. In a rat C6 glioma model, in vivo SPECT demonstrated focal tumour accumulation, which was corroborated by ex vivo autoradiography; immunofluorescence confirmed P2X7R expression in GAMMs. Histopathology (H&E) and mouse-to-human dosimetry supported a favourable safety profile and the clinical translation potential of [131I]FJR01. In addition, [131I]FJR01 is well suited as a probe for competitive binding assays to screen next-generation P2X7R-targeted ligands.
Insights
Researchers developed a novel SPECT tracer, [131I]FJR01, targeting the P2X7 receptor (P2X7R) for glioblastoma-associated microglia/macrophages (GAMMs) imaging. This tracer shows promising tumor uptake and safety for clinical translation.
Area of Science:
- Neuroscience
- Molecular Imaging
- Oncology
Background:
- The P2X7 receptor (P2X7R) is a key biomarker for glioblastoma-associated microglia/macrophages (GAMMs).
- Current imaging techniques lack specific SPECT tracers for GAMMs.
- There is a need for novel radiotracers to visualize and target GAMMs in glioblastoma.
Purpose of the Study:
- To design and evaluate novel radioiodinated P2X7R ligands for SPECT imaging of GAMMs.
- To assess the in vitro and in vivo performance of the lead candidate, [131I]FJR01.
- To determine the potential of [131I]FJR01 for glioblastoma imaging and drug discovery.
Main Methods:
- Design of P2X7R analogues (FJR01, FJR02) based on a high-affinity scaffold and molecular docking.
- In vitro screening using cell lines expressing human or mouse P2X7R.
- Radioiodination of FJR01 to yield [131I]FJR01, followed by in vitro stability assessment.
- Biodistribution studies in normal mice.
- In vivo SPECT imaging in a rat C6 glioma model.
- Ex vivo autoradiography and immunofluorescence for target validation.
- Histopathology and dosimetry for safety assessment.
Main Results:
- FJR01 demonstrated high affinity for human P2X7R (IC50 = 8.8 nM).
- [131I]FJR01 was prepared with high radiochemical yield (95%) and excellent stability.
- Biodistribution showed high brain uptake and rapid clearance in normal mice.
- In vivo SPECT revealed focal tumor accumulation in a rat glioma model.
- Immunofluorescence confirmed P2X7R expression in GAMMs within the tumor.
- Histopathology and dosimetry indicated a favorable safety profile.
Conclusions:
- [131I]FJR01 is a promising SPECT tracer for imaging P2X7R-expressing GAMMs in glioblastoma.
- The tracer exhibits favorable pharmacokinetic properties and tumor-specific accumulation.
- Its safety profile supports potential clinical translation for glioblastoma diagnostics.
- [131I]FJR01 can also serve as a valuable tool for screening new P2X7R-targeted ligands.
