Evaluation of 6-¹¹C-Methyl-m-Tyrosine as a PET Probe for Presynaptic Dopaminergic Activity: A Comparison PET Study with β-¹¹C-l-DOPA and ¹⁸F-FDOPA in Parkinson Disease Monkeys

Abstract

We recently developed a novel PET probe, 6-11 C-methyl-m-tyrosine ( 11 C-6MemTyr), for quantitative imaging of presynaptic dopamine synthesis in the living brain. In the present study, 11 C-6MemTyr was compared with β-11 C-L-DOPA and 6-18 F-fluoro-L-dopa ( 18 F-FDOPA) in the brains of normal and Parkinson disease (PD) model monkeys (Macaca fascicularis). Methods: PD model monkeys were prepared by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and 11 C-β-CFT was applied to assess neuronal damage as dopamine transporter (DAT) availability. 11 C-6MemTyr, β-11 C-L-DOPA, or 18 F-FDOPA was injected with and without carbidopa, a specific inhibitor of peripheral aromatic L-amino acid decarboxylase. In normal and PD monkeys, the dopamine synthesis rates calculated using PET probes were analyzed by the correlation plot with DAT availability in the striatum. Results: In normal monkeys, whole-brain uptake of β-11 C-L-DOPA and 18 F-FDOPA were significantly increased by carbidopa at the clinical dose of 5 mg/kg by mouth. In contrast, 11 C6MemTyr was not affected by carbidopa at this dose, and the metabolic constant value of 11 C-6MemTyr in the striatum was significantly higher than those of the other 2 PET probes. Significant reduction of the presynaptic DAT availability in the striatum was detected in MPTP monkeys, and correlation analyses demonstrated that 11 C-6MemTyr could detect dopaminergic damage in the striatum with much more sensitivity than the other PET probes. Conclusion: 11 C-6MemTyr is a potential PET probe for quantitative imaging of presynaptic dopamine activity in the living brain with PET.

PET Imaging of Mitochondrial Complex I with 18F-BCPP-EF in the Brains of MPTP-Treated Monkeys

“…We previously confirmed that the degeneration of nigrostriatal dopamine neurons was induced by the intravenous administration of MPTP to monkeys over a period of several months and resulted in impaired presynaptic dopamine parameters, as determined by DAT availability, dopamine synthesis, and tyrosine hydroxylase immunoreactivity in the brain (9,10). A previous study reported that although plotting the striatal MTGA Ki values of 11 C-6MemTyr, b-11 C-L-DOPA, and 18 F-FDOPA against the BP ND of 11 C-b-CFT in the striatum of monkeys revealed positive correlations, the Ki value of 11 C-6MemTyr provided greater correlation coefficients than b-11 C-L-DOPA and 18 F-FDOPA (10). The present study also demonstrated that the most sensitive PET probe for the detection of impaired MC-I activity was 11 C-6Mem-Tyr.…”

“…The present study also demonstrated that the most sensitive PET probe for the detection of impaired MC-I activity was 11 C-6Mem-Tyr. The different abilities of b-11 C-L-DOPA, 18 F-FDOPA, and 11 C6MemTyr to detect presynaptic dopamine damage may be attributed to their different metabolic profiles on the basis of catechol-(b-11 C-L-DOPA and 18 F-FDOPA) and noncatechol-type ( 11 C-6MemTyr) structures (10).…”

“…Specific radioactivity was 50.5 6 13.5 GBq/mmol. 11 C-6MemTyr was labeled using the rapid Pd(0)-mediated cross-coupling reaction of 11 Cmethyl iodide and corresponding alkenyl boronate precursor (10,14). Radiochemical purity was greater than 99%, and specific radioactivity was 40.0 6 10.1 GBq/mmol.…”

“…Five male normal and 5 MPTP-treated cynomolgus monkeys (Macaca fascicularis; age range, 2.8-3.3 y; weight range, 2.0-3.5 kg) were subjected to PET scans (9,10). MPTP at doses ranging from 0.2 to 0.4 mg/kg of free base in phosphate-buffered saline was injected intravenously once per week over a 4-mo period until a stable parkinsonian syndrome was observed.…”

“…Quantitative analyses of b-11 C-L-DOPA, 18 F-FDOPA, and 11 C-6MemTyr were conducted by a multitime graphical analysis (MTGA) (10,18,19) applying the time-activity curve in the cerebellum as an input function.…”