Evaluation of dopaminergic terminal loss in a Parkinson's disease rat model, [18F]FDOPA versus [18F]FMT microPET.

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson’s disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the pre-clinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [18F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18F]FDOPA) and 6-[18F]fluoro-L-m-tyrosine ([18F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, [18F]FMT should be more sensitive to moderate fluctuations of DA activity, and closely related to post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [18F]FMT and [18F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase (AADC) inhibitor. A catechol-O-methyl transferase inhibitor was also given before [18F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method (with the tissue-derived uptake rate constant Kc as outcome). Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [18F]FMT and [18F]FDOPA estimates of decreased uptake in the denervated striatum. However, only [18F]FMT Kc succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study demonstrated the higher sensitivity of [18F]FMT, with respect of [18F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo AADC activity targeting in future investigations on progressive PD models.