Assessment of cerebral drug occupancy in humans using a single PET-scan: A [ 11 C]UCB-J PET study.

Autor: Marstrand-Joergensen MR; Epilepsy Clinic, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen O, 2100, Denmark.; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Rigshospitalet, Building 8057, Blegdamsvej 9, Copenhagen, 8057, DK-2100, Denmark.; Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark.; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Laurell GL; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Rigshospitalet, Building 8057, Blegdamsvej 9, Copenhagen, 8057, DK-2100, Denmark.; Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA.; Department of Psychiatry, Columbia University, New York, NY, USA., Herrmann S; Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark., Nasser A; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Rigshospitalet, Building 8057, Blegdamsvej 9, Copenhagen, 8057, DK-2100, Denmark., Johansen A; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Rigshospitalet, Building 8057, Blegdamsvej 9, Copenhagen, 8057, DK-2100, Denmark.; Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark., Lund A; Department of Neuroanaesthesiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark., Andersen TL; Department of Clinical Physiology & Nuclear Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark.; Department of Clinical Medicine, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., Knudsen GM; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Rigshospitalet, Building 8057, Blegdamsvej 9, Copenhagen, 8057, DK-2100, Denmark.; Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark.; Department of Clinical Medicine, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., Pinborg LH; Epilepsy Clinic, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen O, 2100, Denmark. lars.pinborg@nru.dk.; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Rigshospitalet, Building 8057, Blegdamsvej 9, Copenhagen, 8057, DK-2100, Denmark. lars.pinborg@nru.dk.; Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark. lars.pinborg@nru.dk.; Department of Clinical Medicine, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark. lars.pinborg@nru.dk.
Jazyk: angličtina
Zdroj: European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2024 Sep; Vol. 51 (11), pp. 3292-3304. Date of Electronic Publication: 2024 May 17.
DOI: 10.1007/s00259-024-06759-x
Abstrakt: Purpose: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [ 11 C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals.
Methods: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [ 11 C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model.
Results: SV2A occupancies and V ND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC 50 ), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits.
Conclusion: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC 50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy.
Clinical Trial Registration: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.
(© 2024. The Author(s).)
Databáze: MEDLINE
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