Evaluation of Intraperitoneal [18F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity. (28th October 2022)

• Record Type: Journal Article
• Authors: Halff, Els F.; Natesan, Sridhar; Bonsall, David R.; Veronese, Mattia; Garcia-Hidalgo, Anna; Kokkinou, Michelle; Tang, Sac-Pham; Riggall, Laura J.; Gunn, Roger N.; Irvine, Elaine E.; Withers, Dominic J.; Wells, Lisa A.; Howes, Oliver D.
• Other Names: Vasdev Neil Academic Editor.
• Is Part Of: Molecular imaging. Volume 2022(2022)
• Publication Date: 2022-10-28
• Subjects: Molecular diagnosis -- Periodicals; Diagnostic imaging -- Periodicals; Molecular biology -- Periodicals; Molecular diagnosis; Diagnostic imaging; Molecular biology; Periodicals; 616.075
• DOI: 10.1155/2022/4419221
• Languages: English
• ISSNs: 1535-3508

Abstract

Abstract : Positron emission tomography (PET) using the radiotracer [ 18 F]-FDOPA provides a tool for studying brain dopamine synthesis capacity in animals and humans. We have previously standardised a micro-PET methodology in mice by intravenously administering [ 18 F]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K i Mod of [ 18 F]-FDOPA, using an extended graphical Patlak analysis with the cerebellum as a reference region. This enables a direct comparison between preclinical and clinical output values. However, chronic intravenous catheters are technically difficult to maintain for longitudinal studies. Hence, in this study, intraperitoneal administration of [ 18 F]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [ 18 F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of K i Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of K i Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of K i Mod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by subchronic ketamine. Our results demonstrate that intraperitoneal [ 18 F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on K i Mod estimates (intraperitoneal: 0.024 ± 0.0047 min − 1, intravenous: 0.022 ± 0.0041 min − 1, p = 0.42 ) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity (intraclass correlation coefficient ICC = 0.52, N = 6 ) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated K i Mod as compared to control condition was measured with a large effect size for both methods (intraperitoneal: Cohen's d = 1.3 ; intravenous: Cohen's d = 0.9 ), providing further evidence that ketamine has lasting effects on the dopamine system, which could contribute to its therapeutic actions and/or abuse liability.