Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [18F]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter

Abstract

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.

Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio

“…6). This is in line with previous studies in healthy human subjects [20,21,44,50]. Zanotti-Fregonara and co-workers performed a head-to-head comparison of 18 F-GE-180 with the TSPO PET tracer [ 11 C]PBR28 in healthy subjects and found V T to be about 20 times smaller for 18 F-GE-180 compared to [ 11 C]PBR28 [44].…”

“…Sridharan and co-workers, performing dynamic 18 F-GE-180 PET with arterial blood sampling and metabolite correction in 6 patients with multiple sclerosis, 3 HAB and 3 MAB, found V T in whole brain (excluding lesions) to be about 70% larger in HAB compared to MAB (estimated from fig. 5e in the publication) [50]. In contrast, Feeney and co-workers, Fig.…”

“…Sridharan and co-workers, performing dynamic 18 F-GE-180 PET with arterial blood sampling and metabolite correction in 6 patients with multiple sclerosis, 3 HAB and 3 MAB, found V T in whole brain (excluding lesions) to be about 70% larger in HAB compared to MAB (estimated from fig. 5e in the publication) [ 50 ]. In contrast, Feeney and co-workers, performing dynamic 18 F-GE-180 PET with arterial blood sampling and metabolite correction in 10 healthy volunteers, 5 HAB and 5 MAB, found no significant effect of the TSPO gene polymorphism on any regional V T [ 21 ].…”

“…In response, Albert and co-workers summarized the evidence of the validity of 18 F-GE-180 as TSPO tracer also in humans [ 56 ] (s. also [ 57 ]). Recently, Sridharan and co-workers confirmed specific binding of 18 F-GE-180 in humans by a blocking study in patients with multiple sclerosis showing that in HAB subjects about 57% of V T represent specific binding of 18 F-GE-180 to the TSPO [ 50 ]. Simplified methods for quantitative analysis of 18 F-GE-180 as discussed here might facilitate future studies to further evaluate 18 F-GE-180 in humans.…”

Letter to the Editor re: Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [18F]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter

“…We read with great interest the recent article of Sridharan et al, in which they investigated the specific binding of [ 18 F]GE-180 in a population of subjects with multiple sclerosis [1]. By using pharmacological blockade with XBD173, they were able to confirm in vivo for the first time the presence of specific binding of [ 18 F]GE-180 in the living human brain.…”