Noninvasive quantification of SIRT1 expression–activity and pharmacologic inhibition in a rat model of intracerebral glioma using 2-[18F]BzAHA PET/CT/MRI. Issue 1 (16th January 2020)

• Record Type: Journal Article
• Authors: Laws, Maxwell T; Bonomi, Robin E; Gelovani, David J; Llaniguez, Jeremy; Lu, Xin; Mangner, Thomas; Gelovani, Juri G
• Is Part Of: Neuro-oncology advances. Volume 2:Issue 1(2020)
• Publication Date: 2020-01-16
• Subjects: epigenetics -- EX-527 -- glioma -- molecular imaging -- SIRT1; 616.99481
• DOI: 10.1093/noajnl/vdaa006
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: Background: Several studies demonstrated that glioblastoma multiforme progression and recurrence is linked to epigenetic regulatory mechanisms. Sirtuin 1 (SIRT1) plays an important role in glioma progression, invasion, and treatment response and is a potential therapeutic target. The aim of this study is to test the feasibility of 2-[ 18 F]BzAHA for quantitative imaging of SIRT1 expression–activity and monitoring pharmacologic inhibition in a rat model of intracerebral glioma. Methods: Sprague Dawley rats bearing 9L ( N = 12) intracerebral gliomas were injected with 2-[ 18 F]BzAHA (300–500 µCi/animal i.v.) and dynamic positron-emission tomography (PET) imaging was performed for 60 min. Then, SIRT1 expression in 9L tumors ( N = 6) was studied by immunofluorescence microscopy (IF). Two days later, rats with 9L gliomas were treated either with SIRT1 specific inhibitor EX-527 (5 mg/kg, i.p.; N = 3) or with histone deacetylases class IIa specific inhibitor MC1568 (30 mg/kg, i.p.; N = 3) and 30 min later were injected i.v. with 2-[ 18 F]BzAHA. PET-computerized tomography-magnetic resonance (PET/CT/MR) images acquired after EX-527 and MC1568 treatments were co-registered with baseline images. Results: Standard uptake values (SUVs) of 2-[ 18 F]BzAHA in 9L tumors measured at 20 min post-radiotracer administration were 1.11 ± 0.058 and had a tumor-to-brainstem SUV ratio of 2.73 ± 0.141. IF of 9L gliomas revealed heterogeneous upregulation of SIRT1, especially in hypoxic and peri-necrotic regions. Significant reduction in 2-[ 18 F]BzAHA SUV and distribution volume in 9L tumors was observed after administration of EX-527, but not MC1568. Conclusions: PET/CT/MRI with 2-[ 18 F]BzAHA can facilitate studies to elucidate the roles of SIRT1 in gliomagenesis and progression, as well as to optimize therapeutic doses of novel SIRT1 inhibitors.