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Journal of Nuclear Medicine Vol. 50 No. 6 900-908
© 2009 by Society of Nuclear Medicine
doi: 10.2967/jnumed.108.058552

Clinical Investigation

Kinetic Modeling of 11C-SB207145 Binding to 5-HT4 Receptors in the Human Brain In Vivo

Lisbeth Marner1,2, Nic Gillings2,3, Robert A. Comley4, William F.C. Baaré2,5, Eugenii A. Rabiner4, Alan A. Wilson6, Sylvain Houle6, Steen G. Hasselbalch1,2, Claus Svarer1,2, Roger N. Gunn4,7, Marc Laruelle4,8 and Gitte M. Knudsen1,2

1 Neurobiology Research Unit, Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 2 Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 3 PET and Cyclotron Unit, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 4 Clinical Imaging Centre, GlaxoSmithKline, Imperial College London, Hammersmith Hospital, London, United Kingdom; 5 Danish Research Center for Magnetic Resonance, Copenhagen University Hospital, Hvidovre Hospital, Copenhagen, Denmark; 6 Vivian M. Rakoff PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 7 Department of Engineering Science, University of Oxford, Oxford, United Kingdom; and 8 Division of Neurosciences and Mental Health, Imperial College, London, United Kingdom

Correspondence: For correspondence or reprints contact: Lisbeth Marner, Neurobiology Research Unit N9201, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: lisbeth.marner{at}nru.dk

The serotonin 4 receptor (5-HT4 receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT4 receptor radioligand, 11C-SB207145, for in vivo brain imaging with PET in humans. Methods: For evaluation of reproducibility, 6 subjects were scanned twice with 11C-SB207145 on the same day. A further 2 subjects were scanned before and after blocking with the selective 5-HT4 receptor inverse agonist piboserod (SB207266). Arterial blood samples were drawn for the calculation of metabolite-corrected arterial input functions. Regions of interest were delineated automatically on the individual's MR images coregistered to the PET images, and regional time–activity curves were extracted. Quantitative tracer kinetic modeling was investigated with 1- and 2-tissue-compartment models using plasma input functions and the simplified reference tissue model (SRTM). Results: 11C-SB207145 readily entered the brain and showed a distribution consistent with the known localization of the 5-HT4 receptor. Using plasma input models, the time–activity data were well described by the 2-tissue-compartment model in all regions and allowed for the estimate of binding potentials relative to the reference region (BPND: striatum, 3.38 ± 0.72; hippocampus, 0.82 ± 0.19; parietal cortex, 0.30 ± 0.08). Quantification with the 1-tissue-compartment model, 2-tissue-compartment model, and SRTM were associated with good test–retest reproducibility and time stability. However, the SRTM-generated BPND values in the striatum were underestimated by 20%–43% in comparison to the 2-tissue-compartment model. The blocking study with piboserod confirmed that the radioligand was selective for the 5-HT4 receptor, that the cerebellum was a suitable reference region devoid of specific binding, and that nonspecific binding was constant across brain regions. Conclusion: In vivo imaging of cerebral 5-HT4 receptors can be determined reliably using 11C-207145 PET with arterial input in humans. SRTM showed high reproducibility and reliability but bias in the striatum, and therefore, the use of SRTM should be considered carefully for individual applications.

Key Words: positron emission tomography (PET) • test–retest • blocking • kinetic modeling • quantification

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.


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