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 ${K_i}^{\text{Mod}}$ 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 $K{i}^{\text{Mod}}$ in a within-subject design of both administration routes, (iii) test-retest evaluation of $K{i}^{\text{Mod}}$ in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of $K{i}^{\text{Mod}}$ 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 $K{i}^{\text{Mod}}$ estimates (intraperitoneal: $0.024\pm 0.0047{\min }^{-1}$ , intravenous: $0.022\pm 0.0041{\min }^{-1}$ , $p=0.42$ ) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity ( $\text{intraclass}\text{correlation}\text{coefficient}\left(\text{ICC}\right)=0.52$ , $N=6$ ) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated ${K_i}^{\text{Mod}}$ 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.