Biology subjects

De Feyter, H. M.

Publications and source records attributed to De Feyter, H. M..

3 recordsLinked to original sources

bioRxiv2026

Preclinical Evaluation of Itareparib, a brain penetrant PARP1-selective radioligand, in Glioma Rat Model and Nonhuman Primate

Rationale: Poly(ADP-ribose) polymerase-1 (PARP1) is a central mediator of DNA damage response and is upregulated in glioma, supporting it as a molecular imaging biomarker. However, quantitative PET assessment of PARP1 in infiltrative tumors with a preserved blood-brain barrier remains an unmet need. In this study, we evaluated if [18F]Itareparib, a brain-penetrant, non-trapping, PARP1-selective radioligand with reversible kinetics, could improve brain tumor diagnosis and enable target occupancy studies in neurooncology. Methods: [18F]Itareparib was synthesized and evaluated in an orthotopic rat model of BT142 IDH1-mutant gliomas. Dynamic PET scans were performed with or without the administration of the PARP1-selective inhibitor AZD9574. Standardized uptake value ratios (SUVRs) for tumors were calculated using the contralateral region as reference and compared with distribution volume ratios (DVRs) calculated using kinetic modeling. PARP1-specific binding and tracer stability were assessed using autoradiography, immunofluorescence, biodistribution, and radiometabolite analysis. Brain kinetics of [18F]Itareparib were evaluated in a healthy nonhuman primate (NHP) at baseline and blocking conditions. Results: [18F]Itareparib rapidly entered the rat brains and showed 4-fold higher uptake in BT142 tumors than in the contralateral brain. AZD9574 reduced tumor uptake by 77%, supporting the PARP1-specific binding of [18F]Itareparib in the tumors. SUVR(30-60 min) showed the closest agreement with DVR. Autoradiographic tumor-to-reference mean ratio was 7.3, and AZD9574 reduced the tumor-to-reference ratio by 56%. PARP1 immunofluorescence was higher in tumor than the rest of the brain and correlated with autoradiographic results. In rats, the parent fraction of [18F]Itareparib exceeded 99% in brain through 60 min post tracer injection (p.i.) and was approximately 88% in plasma at 60 min p.i. In the NHP, [18F]Itareparib showed rapid brain uptake, and VT decreased by 21+/-6 % after blocking with AZD9574. Conclusion: [18F]Itareparib showed brain penetration, high in vivo metabolic stability, reversible binding kinetics, and PARP1-specific tumor uptake. These findings support further development of [18F]Itareparib for the quantitative PET imaging of PARP1 in brain tumors.

cancer biology↗

bioRxiv2026

Challenges and Solutions in Quantifying Brain β-Hydroxybutyrate (BHB) with 1H-MRS Following Oral Keto-Ester Consumption

Purpose{beta}-hydroxybutyrate (BHB), a ketone body and alternative cerebral energy substrate, can be measured in vivo using J-difference edited proton magnetic resonance spectroscopy (1H-MRS). Oral ketone supplementation with substrates such as the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (KME) and 1,3-butanediol (BD) have gained attention as a mechanism to elevate circulating BHB and induce ketosis without dietary restrictions. Elevated brain ketone availability is of growing therapeutic interest as a strategy to support neuronal energetics in conditions such as epilepsy, neurodegenerative disease, and alcohol use disorder (AUD). However, both pathways introduce BD into the bloodstream, which crosses the blood-brain barrier. Critically, BD exhibits a spectral signature that closely resembles the prominent BHB peak in JDE-MR spectroscopic imaging (MRSI), identified in a pilot AUD study. MethodsTwo separate JDE-MRSI acquisitions tailored for BHB and BD editing were implemented, exploiting frequency separation between the BHB (4.14ppm) and BD (3.95ppm) coupling partners of the observed 1.2ppm resonance to independently quantify each metabolite. ResultsBrain BD concentrations (0.25-0.58mM) were comparable to or exceeded corresponding BHB concentrations (0.20-0.27mM) in all volunteers after consumption of a single dose of the KME, indicating that BD constitutes a major fraction of the signal conventionally attributed to BHB. Combined BHB+BD concentrations ([~]0.45-0.85mM) were consistent with brain BHB values reported in prior studies employing similar doses of the KME, indicating that those measurements likely reflect a combined BHB+BD signal. ConclusionsSeparate quantification of the two metabolites is important for interpreting brain ketone studies and for understanding the full pharmacology of KME supplementation.

neuroscience↗

bioRxiv2025

Oral Intake of Deuterated Choline at Clinical Dose for Metabolic Imaging of Brain Tumors

Accurate characterization and imaging of brain tumors are essential for effective treatment planning and monitoring. While MRI is widely used because of its high sensitivity for detecting lesions, the range of available types of MR image contrast does not offer high specificity for tumors. Deuterium metabolic imaging (DMI), which combines 2H magnetic resonance spectroscopic imaging (MRSI) with administration of deuterium-labeled substrates, is a relatively new imaging approach that could provide unique, complementary information to anatomical MRI. Preclinical studies have demonstrated the feasibility of DMI with intravenous (IV) administration of deuterated choline (2H9-Cho) for tumor characterization; however, they were performed at doses that exceeded severalfold the daily recommended Cho intake. Here, we investigated the feasibility of oral (PO) administration of 2H9-Cho with a dose set at the recommended upper limit for daily use in humans. DMI was performed in rats with orthotopic glioblastoma tumors following a single, high-dose IV bolus (1 x 285 mg/kg) or low-dose PO administration over three consecutive days (3 x 50 mg/kg). Despite a lower cumulative dose, PO administration resulted in comparable total deuterated Cho (2H9-tCho) concentrations in the tumor, and tumor-to-brain image contrast relative to IV administration. Additionally, 2H and 2D 1H-14N HSQC NMR analyses on excised tumor tissue revealed differences in metabolite contributions to the in vivo 2H9-tCho peak. PO administration led to increased contributions from Cho-derived molecules that were products of tumor metabolism, than during IV infusion of 2H9-Cho. These findings suggest that repeated low-dose PO 2H9- Cho administration can generate high, image contrast between tumor and normal brain, that is predominantly generated by tumor metabolism instead of merely Cho uptake. These results can advance the clinical translation of tCho-DMI as a noninvasive imaging tool for brain tumor characterization by demonstrating the feasibility of an oral intake approach using a clinically relevant dose. Given that Cho is already a widely used and well-tolerated nutritional supplement, oral Cho administration offers a practical, noninvasive alternative to IV infusion that could be conducted alongside regular MRI.

cancer biology↗