Thomas Keller1, Francisco R López-Picón2, Anna Krzyczmonik3, Sarita Forsback4, Anna K Kirjavainen3, Jatta S Takkinen2, Obada Alzghool2, Johan Rajander5, Simo Teperi6, Fanny Cacheux7, Annelaure Damont7, Frédéric Dollé7, Juha O Rinne8, Olof Solin9, Merja Haaparanta-Solin2. 1. Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Finland. Electronic address: tomkel@utu.fi. 2. PET Preclinical Imaging Laboratory, Turku PET Centre, University of Turku, Finland; MediCity Research Laboratory, University of Turku, Finland. 3. Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Finland. 4. Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Finland; Department of Chemistry, University of Turku, Finland. 5. Accelerator Laboratory, Turku PET Centre, Åbo Akademi University, Finland. 6. Department of Biostatistics, University of Turku, Finland. 7. CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France. 8. Turku PET Centre, Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland. 9. Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Finland; Department of Chemistry, University of Turku, Finland; Accelerator Laboratory, Turku PET Centre, Åbo Akademi University, Finland.
Abstract
INTRODUCTION: Neuroinflammation is associated with several neurological disorders, including Alzheimer's disease (AD). The translocator protein 18 kDa (TSPO), due to its overexpression during microglial activation and relatively low levels in the brain under normal neurophysiological conditions, is commonly used as an in vivo biomarker for neuroinflammation. Reported here is the preclinical evaluation of [18F]F-DPA, a promising new TSPO-specific radioligand, as a tool for the detection of activated microglia at different ages in the APP/PS1-21 mouse model of AD and a blocking study to determine the specificity of the tracer. METHODS: [18F]F-DPA was synthesised by the previously reported electrophilic 18F-fluorination methodology. In vivo PET and ex vivo brain autoradiography were used to observe the tracer distribution in the brains of APP/PS1-21 and wildtype mice at different ages (4.5-24 months). The biodistribution and degree of metabolism of [18F]F-DPA were analysed and the specificity of [18F]F-DPA for its target was determined by pre-treatment with PK11195. RESULTS: The in vivo PET imaging and ex vivo brain autoradiography data showed that [18F]F-DPA uptake in the brains of the transgenic animals increased with age, however, there was a drop in the tracer uptake at 19 mo. Despite the slight increase in [18F]F-DPA uptake with age in healthy animal brains, significant differences between wildtype and transgenic animals were seen in vivo at 9 months and ex vivo already at 4.5 months. The specificity study demonstrated that PK11195 can be used to significantly block [18F]F-DPA uptake in all the brain regions studied. CONCLUSIONS: In vivo time activity curves plateaued at approximately 20-40 min suggesting that this is the optimal imaging time. Significant differences in vivo are seen at 9 and 12 mo. Due to the higher resolution, ex vivo autoradiography with [18F]F-DPA can be used to visualise activated microglia at an early stage of AD pathology.
INTRODUCTION: Neuroinflammation is associated with several neurological disorders, including Alzheimer's disease (AD). The translocator protein 18 kDa (TSPO), due to its overexpression during microglial activation and relatively low levels in the brain under normal neurophysiological conditions, is commonly used as an in vivo biomarker for neuroinflammation. Reported here is the preclinical evaluation of [18F]F-DPA, a promising new TSPO-specific radioligand, as a tool for the detection of activated microglia at different ages in the APP/PS1-21 mouse model of AD and a blocking study to determine the specificity of the tracer. METHODS: [18F]F-DPA was synthesised by the previously reported electrophilic 18F-fluorination methodology. In vivo PET and ex vivo brain autoradiography were used to observe the tracer distribution in the brains of APP/PS1-21 and wildtype mice at different ages (4.5-24 months). The biodistribution and degree of metabolism of [18F]F-DPA were analysed and the specificity of [18F]F-DPA for its target was determined by pre-treatment with PK11195. RESULTS: The in vivo PET imaging and ex vivo brain autoradiography data showed that [18F]F-DPA uptake in the brains of the transgenic animals increased with age, however, there was a drop in the tracer uptake at 19 mo. Despite the slight increase in [18F]F-DPA uptake with age in healthy animal brains, significant differences between wildtype and transgenic animals were seen in vivo at 9 months and ex vivo already at 4.5 months. The specificity study demonstrated that PK11195 can be used to significantly block [18F]F-DPA uptake in all the brain regions studied. CONCLUSIONS: In vivo time activity curves plateaued at approximately 20-40 min suggesting that this is the optimal imaging time. Significant differences in vivo are seen at 9 and 12 mo. Due to the higher resolution, ex vivo autoradiography with [18F]F-DPA can be used to visualise activated microglia at an early stage of AD pathology.
Authors: Thomas Keller; Francisco R López-Picón; Anna Krzyczmonik; Sarita Forsback; Jatta S Takkinen; Johan Rajander; Simo Teperi; Frédéric Dollé; Juha O Rinne; Merja Haaparanta-Solin; Olof Solin Journal: J Cereb Blood Flow Metab Date: 2019-05-29 Impact factor: 6.200
Authors: Jinbin Xu; Jianjun Sun; Richard J Perrin; Robert H Mach; Kelly R Bales; John C Morris; Tammie L S Benzinger; David M Holtzman Journal: Ann Clin Transl Neurol Date: 2019-07-09 Impact factor: 4.511
Authors: Lingling Zhang; Kuan Hu; Tuo Shao; Lu Hou; Shaojuan Zhang; Weijian Ye; Lee Josephson; Jeffrey H Meyer; Ming-Rong Zhang; Neil Vasdev; Jinghao Wang; Hao Xu; Lu Wang; Steven H Liang Journal: Acta Pharm Sin B Date: 2020-08-25 Impact factor: 11.413
Authors: Francisco R López-Picón; Thomas Keller; Diana Bocancea; Jatta S Helin; Anna Krzyczmonik; Semi Helin; Annelaure Damont; Frédéric Dollé; Juha O Rinne; Merja Haaparanta-Solin; Olof Solin Journal: Mol Imaging Biol Date: 2021-09-20 Impact factor: 3.488
Authors: Aisling M Chaney; Francisco R Lopez-Picon; Sophie Serrière; Rui Wang; Daniela Bochicchio; Samuel D Webb; Matthias Vandesquille; Michael K Harte; Christina Georgiadou; Catherine Lawrence; Julie Busson; Johnny Vercouillie; Clovis Tauber; Frédéric Buron; Sylvain Routier; Tristan Reekie; Anniina Snellman; Michael Kassiou; Johanna Rokka; Karen E Davies; Juha O Rinne; Dervis A Salih; Frances A Edwards; Llwyd D Orton; Stephen R Williams; Sylvie Chalon; Hervé Boutin Journal: Theranostics Date: 2021-05-03 Impact factor: 11.556