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The Parkinson's-Reversing Breakthrough

Parkinson Disease Therapy

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Abbreviations. DA, dopamine; PD, Parkinson's disease; UPDRS, Unified Parkinson's Disease Rating Scale.

dopamine neuronal numbers and imaging outcomes, there is good correlation between dopamine neuron loss and 18F-DOPA uptake, although conclusions are limited by a very small sample size of only five subjects (12). Numerous other studies have shown that the vesicular transporter and dopamine transporter are reduced in the striatum in postmortem brain from PD patients (23-25). In turn, numerous clinical imaging studies have shown reductions in 18F-DOPA, 11C-VMAT2, and DAT lig-and uptake in PD patients and aging healthy subjects, consistent with the expected pathology of PD and of normal aging. Specifically, these imaging studies demonstrate progressive, asymmetric, putamen greater than caudate—loss of dopaminergic uptake (26-28) (Table 1). In addition, both 11C-VMAT2 and DAT ligands demonstrate reductions in activity with normal aging (13,29).

Imaging with 18F-DOPA, 11C-VMAT2, and DAT ligands target different components of the presynaptic nigrostriatal neuron. The mechanism of each of these lig-ands has been elucidated in preclinical studies. Imaging with 18F-DOPA depends on conversion of 18F-DOPAby aromatic amino acid decarboxylase and uptake and trapping of 18F-dopamine into synaptic vesicles. Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown a correlation between the

18F-DOPA uptake and both dopaminergic neurons in the substantia nigra and dopamine levels in the striatum (30). The vesicular monoamine transporter acts to sequester newly synthesized or recovered monoamines (dopamine, serotonin, nor-epinephrine, and histamine) from the cytosol into the synaptic vesicles, thereby protecting the neurotransmitters from catabolism by cytosolic enzymes and packaging them for subsequent exocytotic release (31). VMAT2 ligand uptake is reduced in two commonly used rodent models of PD: the 6-hydroxydopamine-treated rat and the MPTP-treated mouse (32,33). DAT, a protein on the nerve terminal, is responsible for reuptake of dopamine from the synaptic cleft. In MPTP-treated monkeys, the loss of DAT paralleled that of dopamine in the striatum, and in MPTP monkeys treated with nigral implants, recovery of behavioral function was correlated with changes in DAT imaging (34,35).

Several DAT ligands have been developed and used to assess PD and related disorders. Table 2 provides a detailed comparison of the properties of these ligands. This comparison both illustrates the increasing choice of radioligands available and underscores the distinction of those ligands that enable easy quantification of the imaging signal. DAT imaging agents are cocaine analogs with nanomolar affinity at the DAT (36-41). These ligands are chemically modified to alter the rapid metabolism

TABLE 2 Characteristics of Single Photon Emission Computed Tomography Dopamine Transporter Radioligands

SPECT tracer

[123I]ß-CIT

[123I]FP-CIT

99mTc-TRODAT

[123I]Altropane

Time to peak uptake

Protracted

Rapid 2-3 hr

Rapid 2-3 hr

Rapid 0.5-1 hr

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