TY - JOUR
T1 - The P2X7 receptor tracer [11C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis
T2 - a first-in man study
AU - Hagens, Marloes H. J.
AU - Golla, Sandeep S. V.
AU - Janssen, Bieneke
AU - Vugts, Danielle J.
AU - Beaino, Wissam
AU - Windhorst, Albert D.
AU - O'Brien-Brown, James
AU - Kassiou, Michael
AU - Schuit, Robert C.
AU - Schwarte, Lothar A.
AU - de Vries, Helga E.
AU - Killestein, Joep
AU - Barkhof, Frederik
AU - van Berckel, Bart N. M.
AU - Lammertsma, Adriaan A.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Purpose: 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. Methods: 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. Results: 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 (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. Conclusions: This 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.
AB - Purpose: 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. Methods: 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. Results: 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 (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. Conclusions: This 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.
KW - Multiple sclerosis
KW - Neuroinflammation
KW - P2X -receptor
KW - Positron emission tomography
KW - Purinergic signalling
KW - [ C]SMW139
UR - http://www.scopus.com/inward/record.url?scp=85075058501&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00259-019-04550-x
DO - https://doi.org/10.1007/s00259-019-04550-x
M3 - Article
C2 - 31705174
SN - 1619-7070
VL - 47
SP - 379
EP - 389
JO - European journal of nuclear medicine and molecular imaging
JF - European journal of nuclear medicine and molecular imaging
IS - 2
ER -