TY - JOUR
T1 - Preclinical evaluation of [F-18]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors
AU - Golla, S.V.V.
AU - Klein, P.J.
AU - Bakker, J.
AU - Schuit, R.C.
AU - Christiaans, J.A.M.
AU - van der Geest, L.
AU - Kooijman, E.J.M.
AU - Oropeza-Seguias, G.M.
AU - Langermans, J.A.M.
AU - Leysen, J.E.
AU - Boellaard, R.
AU - Windhorst, A.D.
AU - van Berckel, B.N.M.
AU - Metaxas, A.
PY - 2015
Y1 - 2015
N2 - Introduction: The present study was designed to assess whether [18F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([18F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). Methods: Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets. Results: PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the VTof [18F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. Conclusions: PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [18F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.
AB - Introduction: The present study was designed to assess whether [18F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([18F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). Methods: Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets. Results: PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the VTof [18F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. Conclusions: PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [18F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.
U2 - https://doi.org/10.1016/j.nucmedbio.2014.09.006
DO - https://doi.org/10.1016/j.nucmedbio.2014.09.006
M3 - Article
C2 - 25451213
SN - 0969-8051
VL - 42
SP - 205
EP - 212
JO - Nuclear medicine and biology
JF - Nuclear medicine and biology
IS - 2
ER -
