Influence of Obesity on Brain 5-HT6 Receptor Expression: an In-Vivo Study with the PET Radiotracer [18F]2FNQ1P

Preregistration

In 2016, more than 1.9 billion adults were overweight. Estimations based on current trends suggest that approximatively 25 % of the population will be obese in 2025. Better understanding of obesity pathophysiology will help to develop future therapeutics. Using antagonists, agonists or knock-out animals, serotonin subtype 6 receptor (5-HT₆), have shown to be critically involved in appetite reduction and weight loss. However, it is not known if the pathological cascade triggered by obesity modifies 5-HT₆ receptor density in the brain. In this study, we aim to explore the influence of a diet-induced obesity (DIO) rat model on the 5-HT₆ receptor expression using the PET radiotracer [¹⁸F]2FNQ1P. The primary goal is to detect in-vivo changes in the cerebral uptake of the 5-HT₆ radiotracer changes before and after a 10-week DIO, while measuring whole-body fat accumulation with MRI. Using control animals under normal diet, and a genetic obesity model (Zucker rats), the secondary goal is to compare final 5-HT₆ receptor levels between the three groups (DIO, genetic obesity and control diet). In this stage 1 registered report, we provide preliminary results showing the feasibility of our study: i) DIO model was tested and led to 25.5 % increase in fat measured on MRI, ii) regional 5-HT₆ receptor densities were reliably quantified in PET test-retests following tariquidar pre-injection to increase blood-brain barrier passage of the radiotracer [¹⁸F]2FNQ1P. This multimodal imaging study is expected to yield original results for the understanding of the physiopathology of obesity and the implication of 5-HT₆ receptors in this disease.