Abstract
PurposeThe novel PET tracer [11C]SMW139 binds with high affinity to the P2X7 receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [11C]SMW139 in patients with active relapsing remitting multiple sclerosis (RRMS) and healthy controls (HC) and to evaluate its potential to identify in vivo neuroinflammation in RRMS.MethodsFive RRMS patients and 5 age-matched HC underwent 90-min dynamic [11C]SMW139 PET scans, with online continuous and manual arterial sampling to generate a metabolite-corrected arterial plasma input function. Tissue time activity curves were fitted to single- and two-tissue compartment models, and the model that provided the best fits was determined using the Akaike information criterion.ResultsThe optimal model for describing [11C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k4 fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (VT) and binding potential (BPND) in RRMS compared with HC in normal appearing brain regions. BPND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased VT was observed in enhancing lesions, possibly resulting from disruption of the blood-brain barrier in active MS lesions. In addition, there was a high correlation between parameters obtained from 60- to 90-min datasets, although analyses using 60-min data led to a slight underestimation in regional VT and BPND values.ConclusionsThis first in-man study demonstrated that uptake of [11C]SMW139 can be quantified with PET using BPND as a measure for specific binding in healthy controls and RRMS patients. Additional studies are warranted for further clinical evaluation of this novel neuroinflammation tracer.
Highlights
Material and methodsRadiological evaluation of relapsing remitting multiple sclerosis (RRMS) is mainly based on new T2 lesions and active gadolinium-enhancing lesions on magnetic resonance imaging (MRI) [1]
It was shown that the radioligand [11C]SMW139 selectively binds to the P2X7 receptor with high affinity in preclinical in vivo studies and in post-mortem human tissues [8, 12,13,14]
The aims of this study were to evaluate in vivo pharmacokinetic characteristics of [11C]SMW139 and to perform a proof of concept study assessing whether this novel tracer can be used for identifying neuroinflammation in RRMS
Summary
Radiological evaluation of relapsing remitting multiple sclerosis (RRMS) is mainly based on new T2 lesions and active gadolinium-enhancing lesions on magnetic resonance imaging (MRI) [1]. Detection of these disease-specific lesions by MRI only partly demonstrates the underlying pathophysiological processes in MS. The translocator protein 18 kDa (TSPO), present on the mitochondrial membrane of microglial cells, has been used as an in vivo marker of neuroinflammation in several neurological disorders including MS [3,4,5]. It was shown that the radioligand [11C]SMW139 selectively binds to the P2X7 receptor with high affinity in preclinical in vivo studies and in post-mortem human tissues [8, 12,13,14]
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