The P2X₇ receptor tracer [¹¹C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study.

Abstract

The 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. Five 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. The 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 (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. This first in-man study demonstrated that uptake of [¹¹C]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.