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.

Automated summary

This study evaluated intraperitoneal administration of [F-18]-FDOPA as a less invasive alternative to intravenous administration for longitudinal imaging studies. The results showed that intraperitoneal [F-18]-FDOPA administration resulted in good brain uptake and yielded similar estimates of dopamine synthesis capacity as intravenous administration. The technique supported longitudinal studies and demonstrated the lasting effects of subchronic ketamine on the dopamine system.