In the area of molecular imaging for PD, presynaptic tracers play an irreplaceable role in the evaluation of neuron degeneration in substantia nigra. Among those tracers, PET imaging targeting the dopamine active transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) has been reported to have good sensitivity and that its results are closely related to the motor and non-motor symptoms. By contrast, although 18F-DOPA is more convenient for clinical application and can reflect the capability of substantia nigra neurons to synthesize dopamine, its application is still limited due to the report of false-negative results and the factors affecting the imaging results.[13, 14] In this study, we directly compared the PET/CT imaging results of 18F-DTBZ and 18F-DOPA in PD patients. In 18F-DOPA PET/CT imaging, entacapone was administered to inhibit the absorption of the imaging agent in peripheral tissues and thereby improved its imaging quality and consistency. Besides, the visual inspection was assisted by the uptake of putamen in healthy controls. Eventually, both 18F-DOPA and 18F-DTBZ imaging presented no false-negative results. These findings proved that these two tracers are both reliable in PET/CT imaging for PD patients.
18F-DTBZ as a specific imaging agent can specifically bind with VMAT2 in the terminals of substantia nigra neurons to reflect the density of vesicular monoamine in the striatum, so it is recognized as having relatively few interfering factors.[18–20] In previous studies, 18F-DTBZ was considered to have no false-negative results, and the radioactivity uptake of the striatum is related to the clinical stage and the motor and non-motor symptom scores, which can be used to evaluate the apoptosis of substantia nigra neurons. The finding of this study is consistent with the above results and confirmed the reliability of 18F-DTBZ in PET imaging for PD patients.
18F-DOPA as a metabolic imaging agent can be transformed into 18F-dopamine under the action of aromatic amino acid decarboxylase (AADC) and then transported to the striatum. Because 18F-DOPA is a metabolic agent, it can also be absorbed by peripheral tissues for anabolism. Therefore, carbidopa is usually administrated to patients to inhibit AADC activity in peripheral tissues, so as to increase the radioactive concentration in the intracranial blood and better reflect the capability of dopamine synthesis in substantia nigra neurons. Apart from carbidopa, entacapone can also inhibit the uptake of 18F-DOPA in peripheral tissues by inhibiting the activity of catechol-O-methyl transferase, and thereby improve the intracranial concentration of the radioactive tracer and its uptake by striatum.[22, 23] In the current study, we used entacapone instead of carbidopa and also obtained images of good quality.
Previous studies reported that the sensitivity of 18F-DOPA PET/CT imaging to PD diagnosis is 90%-100% and the false negative result can be seen among patients at early stage. However, there is no convincing explanation for the false negative result. Some researchers assumed that the ability of substantia nigra neurons to synthesize dopamine was enhanced under the condition of the insufficient dopamine supply, which leads to false negative results of radioactivity uptake in the striatum. However, this explanation is not consistent with the results of animal experiments. For example, even when a monkey had decreased substantia nigra neurons without motor symptoms, the dopamine concentration in the striatum already decreased significantly, and the SUR in the striatum of 18F-DOPA also decreased. [26, 27]
Studies on animals have proven that the motor symptoms only occur when more than 60% of the substantia nigra neurons are damaged and the concentration of dopamine in striatum decreased significantly.[28–31] In this study, the SUR of the contralateral putamen in PD patients at stage I was about 40% of that in the healthy controls (18F-DTBZ, 38.46%; 18F-DOPA, 40.07%), which is in consistency with the results of animal studies and suggested that both 18F-DOPA and 18F-DTBZ PET/CT imaging can reliably reflect the damage of the substantia nigra neurons. With the progression of PD disease, the radioactivity uptake of the two tracers in the striatum decreased significantly in different rate. The radioactivity uptake of 18F-DTBZ in the striatum decreased more significantly with the progression of PD, indicating the synthetic regulation of substantia nigra neurons.