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Both PET, also called dual photon emission tomography, and SPECT are sensitive methods of measuring in vivo neurochemistry (4,5). The choice of imaging modality is ultimately determined by the specific study questions and study design. Generally, PET cameras have better resolution than SPECT cameras; however, SPECT studies may be technologically and clinically more feasible, particularly for large clinical studies and in clinical practice. PET studies may benefit from greater flexibility in the range of radiopharmaceuticals that can be tested, but SPECT studies have the advantage of longer half-life radiopharmaceuticals necessary for some studies.

The strengths and limitations of in vivo neuroreceptor imaging studies depend on the imaging technology utilized to measure brain neurochemistry and the ligand or biochemical marker used to tag a specific brain neurochemical system. The properties of the radiopharmaceutical are the most crucial issue in developing a useful imaging tool for PD. Some of the key steps in development of a potential radioligand include assessment of its brain penetration, its selectivity for the target site, its binding properties to the site, and its metabolic fate. These properties help to determine the signal-to-noise ratio of the ligand and the ease of quantitation of the imaging signal. Although ligands targeting neuronal metabolism have been used successfully to study PD patients, this review will focus on dopaminergic ligands (6). Specific markers for the dopaminergic system, including 18F-DOPA (7-12), 11C-VMAT2 (13-15), and dopamine transporter (DAT) ligands (16-22), have been widely used to evaluate patients with PD.

Dopamine ligands are useful to assess PD insofar as they reflect the ongoing dopaminergic degeneration in PD. In the study most directly correlating changes in

TABLE 1 Comparison of Dopamine Presynaptic Ligands in Parkinson's Disease Studies

[123I]P-CIT

1C-VMAT2

8F-DOPA

Target

Bilateral reduction in hemi-PD Correlates with UPDRS

in cross section Annual reduction change with aging (% loss from baseline) Annual progression (% loss from baseline)

DA transporter Yes Yes

6-13

Vesicular transporter Yes Yes

DA turnover Yes Yes

No change

7-12

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

8-18 hr

Washout phase

Prolonged

Prolonged

Intermediate

Rapid

DAT binding affinity

1.4nM Ki

3.5 nM Ki

9.7nm Ki

6.62 nM IC50

DAT:SERT selectivity

1.7:1

2.8:1

26:1

28:1

SPECT target:background

tissue ratio

High

High

Low

Low

Abbreviations:Df*T, dopamine transporter; SERT, serotonin transporter; SPECT, single photon emission computed tomography.

Abbreviations:Df*T, dopamine transporter; SERT, serotonin transporter; SPECT, single photon emission computed tomography.

of cocaine at the ester linkage to provide more in vivo stability of the parent compound. Nonetheless, the kinetic properties of DAT radiotracers are quite different with regard to plasma protein binding, permeability across the blood-brain barrier, binding affinity, selectivity, and elimination. These differences are crucial to the applications of the DAT ligand for imaging (42). For example, although a given DAT tracer may distinguish PD from healthy controls based on the qualitative appearance of striatal uptake, the ability to distinguish the longitudinal changes in severity of PD may be more difficult for tracers with relatively poorer signal-to-noise properties (lower specific to nonspecific brain uptake) (Table 2). The quantitative properties of the radiotracer must be well understood to assess disease progression. Specifically, does the imaging signal provide a measure that is related to Bmax, the density of DAT, and/or the integrity of dopamine neurons? For some tracers, absolute quantitation of the DAT signal may require invasive methods involving full kinetic modeling, whereas other DAT tracers have a pharmacokinetic profile, which simplifies the methods for signal quantification. For example, the unusual binding kinetics of [123I]P-carboxymethoxy-iodophenyl tropane (CIT), with a protracted period of stable specific radiotracer uptake in the brain and extremely slow elimination from the DAT sites in striatum, permit reproducible quantitative determination of DAT density using a simple tissue ratio method (19,43). For DAT tracers with faster washout from specific binding sites, this simple ratio technique overestimates the density of binding sites in healthy striatum relative to PD (44), although these tracers may permit better visual discrimination of the diseased from control cases.

Of the DAT SPECT tracers in development, [123I]|3-CIT, [123I]FP-CIT, [123I]-altropane, and [99mTc]-TRODAT have been the most widely evaluated agents for SPECT imaging (18,20,45) and [18F]-CFT (WIN 35,428) for PET (46,47). None of these tracers is commercially available as yet in North America, although one tropane derivative of cocaine (FP-CIT, DATSCAN®) is available as a [123I]-labeled tracer in Europe.

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