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

Positron emission tomography (PET) using the radiotracer [F-18]-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 [F-18]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K-i(Mod) of [F-18]-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 [F-18]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [F-18]-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 [F-18]-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.