Cargando…

First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors

BACKGROUND: Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-d-aspartate (NMDA) receptors have had limited success. [(18)F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity...

Descripción completa

Detalles Bibliográficos
Autores principales: van der Aart, Jasper, Golla, Sandeep S. V., van der Pluijm, Marieke, Schwarte, Lothar A., Schuit, Robert C., Klein, Pieter J., Metaxas, Athanasios, Windhorst, Albert D., Boellaard, Ronald, Lammertsma, Adriaan A., van Berckel, Bart N. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063804/
https://www.ncbi.nlm.nih.gov/pubmed/30054846
http://dx.doi.org/10.1186/s13550-018-0424-2
_version_ 1783342604172132352
author van der Aart, Jasper
Golla, Sandeep S. V.
van der Pluijm, Marieke
Schwarte, Lothar A.
Schuit, Robert C.
Klein, Pieter J.
Metaxas, Athanasios
Windhorst, Albert D.
Boellaard, Ronald
Lammertsma, Adriaan A.
van Berckel, Bart N. M.
author_facet van der Aart, Jasper
Golla, Sandeep S. V.
van der Pluijm, Marieke
Schwarte, Lothar A.
Schuit, Robert C.
Klein, Pieter J.
Metaxas, Athanasios
Windhorst, Albert D.
Boellaard, Ronald
Lammertsma, Adriaan A.
van Berckel, Bart N. M.
author_sort van der Aart, Jasper
collection PubMed
description BACKGROUND: Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-d-aspartate (NMDA) receptors have had limited success. [(18)F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding. The purpose of the present study was to evaluate [(18)F]PK-209 in 10 healthy humans by assessing test–retest reproducibility and binding specificity following intravenous S-ketamine administration (0.5 mg ∙ kg(−1)). Five healthy subjects underwent a test–retest protocol, and five others a baseline-ketamine protocol. In all cases dynamic, 120-min PET scans were acquired together with metabolite-corrected arterial plasma input functions. Additional input functions were tested based on within-subject and population-average parent fractions. RESULTS: Best fits of the brain time-activity curves were obtained using an irreversible two-tissue compartment model with additional blood volume parameter. Mean test–retest variability of the net rate of influx K(i) varied between 7 and 24% depending on the input function. There were no consistent changes in [(18)F]PK-209 PET parameters following ketamine administration, which may be a consequence of the complex endogenous ligand processes that affect channel gating. CONCLUSIONS: The molecular interaction between [(18)F]PK-209 and the binding site within the NMDA receptor ion channel is insufficiently reproducible and specific to be a reliable imaging agent for its quantification. TRIAL REGISTRATION: EudraCT 2014-001735-36. Registered 28 April 2014
format Online
Article
Text
id pubmed-6063804
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-60638042018-08-10 First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors van der Aart, Jasper Golla, Sandeep S. V. van der Pluijm, Marieke Schwarte, Lothar A. Schuit, Robert C. Klein, Pieter J. Metaxas, Athanasios Windhorst, Albert D. Boellaard, Ronald Lammertsma, Adriaan A. van Berckel, Bart N. M. EJNMMI Res Original Research BACKGROUND: Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-d-aspartate (NMDA) receptors have had limited success. [(18)F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding. The purpose of the present study was to evaluate [(18)F]PK-209 in 10 healthy humans by assessing test–retest reproducibility and binding specificity following intravenous S-ketamine administration (0.5 mg ∙ kg(−1)). Five healthy subjects underwent a test–retest protocol, and five others a baseline-ketamine protocol. In all cases dynamic, 120-min PET scans were acquired together with metabolite-corrected arterial plasma input functions. Additional input functions were tested based on within-subject and population-average parent fractions. RESULTS: Best fits of the brain time-activity curves were obtained using an irreversible two-tissue compartment model with additional blood volume parameter. Mean test–retest variability of the net rate of influx K(i) varied between 7 and 24% depending on the input function. There were no consistent changes in [(18)F]PK-209 PET parameters following ketamine administration, which may be a consequence of the complex endogenous ligand processes that affect channel gating. CONCLUSIONS: The molecular interaction between [(18)F]PK-209 and the binding site within the NMDA receptor ion channel is insufficiently reproducible and specific to be a reliable imaging agent for its quantification. TRIAL REGISTRATION: EudraCT 2014-001735-36. Registered 28 April 2014 Springer Berlin Heidelberg 2018-07-27 /pmc/articles/PMC6063804/ /pubmed/30054846 http://dx.doi.org/10.1186/s13550-018-0424-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
van der Aart, Jasper
Golla, Sandeep S. V.
van der Pluijm, Marieke
Schwarte, Lothar A.
Schuit, Robert C.
Klein, Pieter J.
Metaxas, Athanasios
Windhorst, Albert D.
Boellaard, Ronald
Lammertsma, Adriaan A.
van Berckel, Bart N. M.
First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors
title First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors
title_full First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors
title_fullStr First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors
title_full_unstemmed First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors
title_short First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors
title_sort first in human evaluation of [(18)f]pk-209, a pet ligand for the ion channel binding site of nmda receptors
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063804/
https://www.ncbi.nlm.nih.gov/pubmed/30054846
http://dx.doi.org/10.1186/s13550-018-0424-2
work_keys_str_mv AT vanderaartjasper firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT gollasandeepsv firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT vanderpluijmmarieke firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT schwartelothara firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT schuitrobertc firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT kleinpieterj firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT metaxasathanasios firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT windhorstalbertd firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT boellaardronald firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT lammertsmaadriaana firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors
AT vanberckelbartnm firstinhumanevaluationof18fpk209apetligandfortheionchannelbindingsiteofnmdareceptors