[11C]-DPA-713 and [18F]-DPA-714 as new PET tracers for TSPO: a comparison with [11C]-(R)-PK11195 in a rat model of herpes encephalitis

Abstract

Background: Activation of microglia cells plays an important role in neurological diseases. Positron emission tomography (PET) with [(11)C]-(R)-PK11195 has already been used to visualize activated microglia cells in neurological diseases. However, [(11)C]-(R)-PK11195 may not possess the required sensitivity to visualize mild neuroinflammation. In this study, we evaluated the PET tracers [(11)C]-DPA-713 and [(18)F]-DPA-714 as agents for imaging of activated microglia in a rat model of herpes encephalitis.

Materials and methods: Rats were intranasally inoculated with HSV-1. On day 6 or 7 after inoculation, small animal PET studies were performed to compare [(11)C]-(R)-PK11195, [(11)C]-DPA-713, and [(18)F]-DPA-714.

Results: Uptake of [(11)C]-DPA-713 in infected brain areas was comparable to that of [(11)C]-(R)-PK11195, but [(11)C]-DPA-713 showed lower non-specific binding. Non-specific uptake of [(18)F]-DPA-714 was lower than that of [(11)C]-(R)-PK11195. In the infected brain, total [(18)F]-DPA-714 uptake was lower than that of [(11)C]-(R)-PK11195, with comparable specific uptake.

Conclusions: [(11)C]-DPA-713 may be more suitable for visualizing mild inflammation than [(11)C]-(R)-PK11195. In addition, the fact that [(18)F]-DPA-714 is an agonist PET tracer opens new possibilities to evaluate different aspects of neuroinflammation. Therefore, both tracers warrant further investigation in animal models and in a clinical setting.

Fig. 1.

Synthesis of DPA-713 from the labeling precursor compound 1 and DPA-714 from the labeling precursor compound 3. The labeling precursor compound 3 and the reference material for DPA-714 were synthesized from compound 1 using ethyleneglycol ditosylate and 2-fluoroethyltosylate as the alkylating agent, respectively.

Fig. 2.

Images (×400) of immunohistochemical staining of microglia cells with Iba, on day 7 after inoculation. For rats infected with HSV-1 (HSE) microglia are shown in the bulbus olfactorius, frontal cortex, hippocampus, cerebellum, and brainstem (a–e). For control rats, only the brainstem (f) is shown. The staining in this brain area is representative for the staining in all other brain areas of control rats.

Fig. 3.

Time–activity curves (left) of the brainstem for [¹¹C]-(R)-PK11195 (a), [¹¹C]-DPA-713 (b), and [¹⁸F]-DPA-714 (c), and small animal PET images (right) of control rats (control), rats infected with HSV-1 (HSE), and rats infected with HSV-1 injected with 5 mg/kg PK11195 5 min before tracer injection (HSE + PK11195). The time–activity curves are expressed as tissue uptake divided by the ex vivo plasma uptake at t = 60 for [¹¹C]-(R)-PK11195 and [¹¹C]-DPA-713, and at t = 120 for [¹⁸F]-DPA-714. Statistically significant differences are indicated by *p < 0.05 and †p < 0.005. The small animal PET images display a coronal plane of the rat head at the level of the brainstem, in which the brain is delineated by a dashed line. The images are summed images between 16 and 60 min for [¹¹C]-(R)-PK11195 and [¹¹C]-DPA-713, and between 12 and 120 min for [¹⁸F]-DPA-714.

Fig. 4.

Correlation of specific binding in control rats for [¹¹C]-(R)-PK11195, [¹¹C]-DPA-713, and [¹⁸F]-DPA-714 with [³H]-PK11195 binding as determined by Kurumaji et al. [25]. The R was 0.96 for [¹¹C]-(R)-PK11195 (p = 0.0006; y = 0.36 + 0.010x), 0.87 for [¹¹C]-DPA-713 (p = 0.0116; y = 1.79 + 0.016x), and 0.77 for [¹⁸F]-DPA-714 (p = 0.0427; y = 1.35 + 0.005x).