Monitoring DHA and AA Brain Uptake in ApoE4 Mice with 18F‐Fluorinated PET Tracers. (20th December 2022)

• Record Type: Journal Article
• Authors: Duro, Marlon Vincent V.; Van Valkenburgh, Juno S.; Kerman, Bilal E.; Wang, Shaowei; Liu, Xiaodan; Sta, Naomi; Zanderigo, Francesca; Jacobs, Russell E.; Chen, Kai; Yassine, Hussein N.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 5
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.065802
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Polyunsaturated fatty acids (PUFAs) are the precursors of various lipid mediators of inflammation. Brain imaging techniques for monitoring the brain's uptake of PUFAs would not only uncover the effects of risk factors for excessive neuroinflammation associated with Alzheimer's disease (AD) and related dementia but also direct the development of methods to prevent or treat AD. Radiosynthesized 11 C‐docosahexaenoic acid (DHA) and 11 C‐arachidonic acid (AA) have already been utilized in positron emission tomography (PET) studies in humans [1, 2]. Because 18 F has a longer half‐life than 11 C, fluorinated PUFA derivatives would be more favorable alternatives for PET studies of brain uptake. Methods: We prepared 18 F‐fluorinated analogues of DHA ( 18 F‐FDHA) and AA ( 18 F‐FAA) as PUFA PET tracers. Radiosynthesis was performed via a nucleophilic fluorination scheme using the tosylate ester derivatives as precursors. We then performed bolus injection of each tracer into 16‐month‐old APOE4 knock‐in mice and scanned them by dynamic PET‐MRI over 45 min to assess region‐specific uptake. PUFA uptake kinetics in the cerebral region was evaluated using the time‐dependent activity in the lumen of the right ventricle as the image‐derived input function and using an irreversible two‐tissue compartment model to calculate the incorporation coefficient (Ki ). Results: Both 18 F‐FDHA and 18 F‐FAA were successfully synthesized in high radiochemical purity (≥98%) and were found to be stable in the formulation and mouse serum for 2 hr. The mean Ki values for the cerebral region were determined to be 6.31 ± 0.98 µL mL ‐1 min ‐1 for 18 F‐FDHA ( n = 4) and 6.75 ± 0.68 µL mL ‐1 min ‐1 for 18 F‐FAA ( n = 5). Conclusion: Using an image‐based method with 18 F‐fluorinated PUFA tracers, we were able to determine Ki values for both AA and DHA. The use of these PUFA PET tracers has the potential to elucidate deleterious changes in PUFA metabolism during various phases of AD as well as effects due to dietary interventions and drug treatment. References 1. Yassine, H.N. et al. (2017). DHA brain uptake and APOE4 status: a PET study with [1‐ 11 C]‐DHA. Alzheimers Res Ther 9, 23. 2. Zanderigo, F. et al. (2018). [ 11 C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use. Synapse 72.