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

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 Ki Mod of [18F]-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 [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 subchronic 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 coefficientðICCÞ = 0:52, N = 6) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated Ki 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.