The P2X 7 receptor tracer [ 11 C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study.

Purpose: The novel PET tracer [ ¹¹ C]SMW139 binds with high affinity to the P2X ₇ receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [ ¹¹ C]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.
Methods: Five RRMS patients and 5 age-matched HC underwent 90-min dynamic [ ¹¹ C]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.
Results: The optimal model for describing [ ¹¹ C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k ₄ fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (V _T ) and binding potential (BP _ND ) in RRMS compared with HC in normal appearing brain regions. BP _ND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased V _T 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 V _T and BP _ND values.
Conclusions: This first in-man study demonstrated that uptake of [ ¹¹ C]SMW139 can be quantified with PET using BP _ND 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.