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Evaluation of intraperitoneal [18F]-FDOPA administration for micro-PET imaging in mice and assessment of the effect of sub-chronic ketamine dosing on dopamine synthesis capacity

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Els Halff, Sridhar Natesan, David R. Bonsall, Mattia Veronese, Anna Garcia-Hidalgo, Michelle Kokkinou, Sac-Pham Tang, Laura Riggall , Roger Gunn, Elaine Irvine, Dominic Withers, Lisa Wells, Oliver Howes

Original languageEnglish
Article number4419221
JournalMolecular Imaging
Accepted/In press8 Oct 2022

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Abstract

Positron emission tomography (PET) using the radiotracer [18F]-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 [18F]-FDOPA via jugular vein cannulation, and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant KiMod of [18F]-FDOPA, using 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 [18F]-FDOPA was evaluated as a less invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [18F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of KiMod in a within-subject design of both administration routes, (iii) test-retest evaluation of KiMod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of KiMod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by sub-chronic ketamine.
Our results demonstrate that intraperitoneal [18F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on KiMod 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 sub-chronic ketamine administration, elevated KiMod 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.

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