Development and Characterization of a Novel Carbon-11 Labeled Positron Emission Tomography Radiotracer for Neuroimaging of Sirtuin 1 with Benzoxazine-Based Compounds

Abstract

Introduction

Sirtuins (SIRTs) comprise a group of histone deacetylase enzymes crucial for regulating metabolic pathways and contributing significantly to various disease mechanisms. Sirtuin 1 (SIRT1), among the seven known mammalian homologs, is extensively investigated and understood, playing a key role in neurodegenerative disorders and cancer. This study focuses on potential as a therapeutic target for conditions such as Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD).

Methods

Utilizing positron emission tomography (PET) as a noninvasive molecular imaging modality, we aimed to expedite the validation of a promising sirtuin 1 inhibitor for clinical trials. However, the absence of a validated sirtuin 1 PET radiotracer impedes clinical translation. We present the development of [¹¹C]1, and ¹¹C-labeled benzoxazine-based derivative, as a lead imaging probe. The radiosynthesis of [¹¹C]1 resulted in a radiochemical yield of 31 ± 4%.

Results

Baseline studies demonstrated that [¹¹C]1 exhibited excellent blood-brain barrier (BBB) penetration capability, with uniform accumulation throughout various brain regions. Self-blocking studies revealed that introducing an unlabeled compound 1, effectively blocking sirtuin 1, led to a substantial reduction in whole-brain uptake, emphasizing the in vivo specificity of [¹¹C]1 for sirtuin 1.

Discussion

The development of [¹¹C]1 provides a valuable tool for noninvasive imaging investigations in rodent models with aberrant sirtuin 1 expression. This novel radiotracer holds promise for advancing our understanding of sirtuin 1’s role in disease mechanisms and may facilitate the validation of sirtuin 1 inhibitors in clinical trials.

Keywords:

• sirtuin 1
• neuroimaging
• benzoxazine-based derivative
• blood-brain barrier

Ethics Statement

Compliance with ethical standards.

Acknowledgments

We extend our gratitude to the dedicated staff at the Martinos Center for their invaluable assistance with radiosynthesis and rodent experiments. This work received generous support from the National Institutes of Health (NIH) under grant AG015379 (C.W.). The imaging studies were conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, utilizing resources made available by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Regional Resource generously supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the NIH.

We would also like to acknowledge the instrumental role played by NIH Shared Instrumentation Grant Program and High-End Instrumentation Grant Program, specifically grant numbers: S10OD025234, S10RR017208, S10RR026666, S10RR022976, S10RR019933, S10RR023401, and S10OD023517, in providing access to the necessary instrumentation for this research.

Disclosure

The authors declare no competing interests in this work.