Novel non-invasive methodology to map TSPO PET tracers blood-to-brain influx rate

Background: Neuroinflammation is a critical feature across various brain disorders, including neurological and neurodegenerative conditions such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease, as well as neuropsychiatric disorders like major depressive disorder and schizophrenia. Positron emission tomography (PET) targeting the 18-kDa translocator protein (TSPO) is the primary tool for in vivo imaging of neuroinflammation. However, significant methodological challenges have limited the development of reliable biomarkers. Objective: This study aimed to advance non-invasive TSPO PET imaging by using a novel blood-free methodology for estimating the blood-to-brain influx rate constant (K1). The objective was to validate this approach using the first-generation [11C]-PK11195 and the second generation [11C]-PBR28 TSPO radiotracers, and to extend it to voxel-level analysis. The primary hypothesis posited that elevated levels of peripheral inflammation would negatively correlate with K1, indicating reduced delivery of TSPO tracers to the brain. Methods: A novel non-invasive method utilizing an image-derived input function (IDIF) was employed to estimate the blood-to-brain influx rate constant (K1) and generate parametric maps. Analyses were conducted at both regional and voxel levels. The method was validated across datasets representing various psychiatric conditions, including major depressive disorder and schizophrenia. Additionally, the impact of peripheral inflammatory markers, body weight and gender on K1 was systematically assessed. Results: The methodology was successfully applied to all tracers under investigation and effectively generated meaningful K1 parametric maps. The study confirmed the hypothesized negative correlation between peripheral inflammation and K1. Remarkably, the parameter was not influenced by the psychiatric disease. Additionally, significant effects of body weight and gender on K1 were observed. Conclusion: This work represents a significant advancement in TSPO PET imaging by providing a reliable, non-invasive method for mapping the blood-to-brain influx of TSPO radiotracers. The study confirms the hypothesis that increased peripheral inflammation is associated with reduced TSPO tracer delivery to the brain and supports the emerging model of peripheralto- central immune interaction. By accounting for key variables such as body weight, gender, and peripheral inflammatory status, this research offers crucial insights and improves the potential for biomarker validation in psychiatric disorders. This methodological advancement is pivotal for enhancing the interpretability of TSPO PET measures and advancing the field of neuroinflammation imaging.