PurposeOver the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in  many neurodegenerative diseases, including Alzheimer’s disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [18F]GE-180 and [18F]DPA-714 with (R)-[11C]PK11195 in a rodent model of subtle focal inflammation.ProceduresAdult male Wistar rats were stereotactically injected with 1 μg lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[11C]PK11195 and [18F]GE-180 (n = 6) or [18F]DPA-714 (n = 6). Ten animals were scanned with either [18F]GE-180 (n = 5) or [18F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BPND. Autoradiography and immunohistochemistry were performed to confirm in vivo results.ResultsAt 40–60 min post-injection, [18F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R)-[11C]PK11195 (3.41 ± 1.09 vs. 2.43 ± 0.39, p = 0.03); [18]DPA-714 did not (2.80 ± 0.69 vs. 2.26 ± 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BPND) in the core of the LPS injection site with [18F]GE-180 but not with [18F]DPA-714 vs. (R)-[11C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BPND.ConclusionsSecond-generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [18F]GE-180 shows a higher core/contralateral ratio and BPND when compared to (R)-[11C]PK11195, while [18F]DPA-714 did not.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-0984-3) contains supplementary material, which is available to authorized users.

Purpose: Measurements of non-displaceable binding (V ND ) of positron emission tomography (PET) ligands are not often made in vivo in humans because they require ligands to displace binding to target receptors and there are few readily available, safe ones to use. A technique to measure V ND for ligands for the 18-kDa translocator protein (TSPO) has recently been developed which compares the total volume of distribution (V T ) before and after administration of the TSPO ligand XBD173. Here, we used XBD173 with an occupancy plot to quantify V ND for two TSPO radiotracers, [ 18 F]GE-180 and [ 11 C]PBR28, in cohorts of people with multiple sclerosis (MS). Additionally, we compared plots of subjects carrying high (HAB) or mixed binding (MAB) affinity polymorphisms of TSPO to estimate V ND without receptor blockade. Procedures: Twelve people with MS underwent baseline MRI and 90-min dynamic [ 18 F]GE-180 PET or [ 11 C]PBR28 PET (n = 6; three HAB, three MAB each). Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model. V ND was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173) and the polymorphism plot (by modelling the differences in signal across presence and absence of rs6971 genotypes). Results: Whole brain V T (mean ± standard deviation) was 0.29 ± 0.17 ml/cm 3 for [ 18 F]GE-180 and 5.01 ± 1.88 ml/cm 3 for [ 11 C]PBR28. Using the occupancy and polymorphism plots respectively, V ND for [ 18 F]GE-180 was 0.11 ml/cm 3 (95 % CI = 0.02, 0.16) and 0.20 ml/cm 3 (0.16, 0.34), accounting for, on average, 55 % of V T in the whole brain. For [ 11 C]PBR28, these values were 3.81 ml/cm 3 (3.02, 4.21) and 3.49 ml/cm 3 (1.38, 4.27), accounting for 67 % of average whole brain V T .Sujata Sridharan and Joel Raffel are joint first authors. Conclusions:Although V T for [ 18 F]GE-180 is low, indicating low brain penetration, half the signal shown by MS subjects reflected specific TSPO binding. V T for [ 11 C]PBR28 was higher and two thirds of the binding was non-specific. No brain ROIs were devoid of specific signal, further confirming that true reference tissue approaches are potentially problematic for estimating TSPO levels.

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