Comparative assessment of 6‐[¹⁸F]fluoro‐L‐m‐tyrosine and 6‐[¹⁸F]fluoro‐L‐dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model

Abstract

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 preclinical 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 [ F]fluoro-3,4-dihydroxyphenyl-L-alanine ([ F]FDOPA) and 6-[ F]fluoro-L-m-tyrosine ([ F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [ F]FMT and [ F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [ F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [ F]FMT and [ F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant K . However, only [ F]FMT K succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [ F]FMT could be more sensitive, with respect of [ F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L-aromatic amino acid decarboxylase activity targeting in future investigations on progressive PD models.

Does dopamine synthesis capacity predict individual variation in curiosity?

“…As such, metabolites can cross the blood-brain-barrier and will distribute throughout the brain in a uniform fashion. This enhances background noise relative to the use of for example [ 18 F]FMT, which is not a substrate for COMT (Becker et al, 2017), leading to a lower signal-to-noise ratio. It should be noted that this would mainly be a concern when the regions of interests are located in brain areas with low dopamine levels, but less so in the dopamine-rich striatum.…”

“…However, this would mostly be a concern for extended scanning times, as [ 18 F]DOPA behaves as an irreversibly bound tracer in the first 90 minutes after tracer injection, during which their uptake rates are tightly correlated (Becker et al, 2017;Doudet et al, 1999).…”

The cognitive effects of a promised bonus do not depend on dopamine synthesis capacity

“…36 . However, this would mostly be a concern for extended scanning times, as [ 18 F]DOPA behaves as an irreversibly bound tracer in the first 90 min after tracer injection, during which their uptake rates are tightly correlated 34,35 . www.nature.com/scientificreports/ Another possibility is that the discrepancy between the original and the current study was introduced by group differences in sample characteristics.…”

“…[ 18 F]DOPA is a substrate for catechol-O-methyltransferase (COMT) in the periphery. Metabolites can cross the blood–brain-barrier and will distribute evenly throughout the brain, enhancing background noise relative to the use of [ 18 F]FMT, which is not a substrate for COMT 34 . However, this is mainly a concern when one is interested in brain areas with low dopamine levels, as opposed to the dopamine-rich striatum.…”

“…Indeed, differences in aging effects on dopamine synthesis capacity measured with [ 18 F]DOPA and [ 18 F]FMT have been observed, possibly owing to age-related changes in post-AADC metabolism 36 . However, this would mostly be a concern for extended scanning times, as [ 18 F]DOPA behaves as an irreversibly bound tracer in the first 90 min after tracer injection, during which their uptake rates are tightly correlated 34 , 35 .…”