Danish Medical Bulletin - No. 2. May 2009. Vol. 56 Page 95

ABSTRACT OF DISSERTATION

Molecular brain imaging of the serotonin system:

Reproducibility and evaluation of PET radiotracers

Lisbeth Marner, MD

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This PhD dissertation was accepted by the Faculty of Health Sciences of the University of Copenhagen, and defended on March 13th 2009.

Official opponents: Lars Friberg, Richard E. Carson, USA, and Ian Law.

Tutors: Gitte Moos Knudsen and Steen G. Hasselbalch.

Correspondence: Lisbeth Marner, Thurebyholmvej 10, 2700 Brønshøj, Denmark.

E-mail: lisbeth@marner.dk

ABSTRACT

The serotonin system is involved not only in psychiatric and neurological diseases, but also in normal behavior, personality and cognition. Positron emission tomography (PET) with selective serotonin ligands has emerged as a key technique for assessing the status of serotonin systems in healthy brain and in diverse neuropsychiatric conditions. This dissertation evaluates methodological aspects of quantitative PET investigations with [ 18 F]altanserin that binds to the serotonin 2A (5-HT 2A ) receptors and a throughout validation of a novel radiotracer [ 11 C]SB207145 that binds to the serotonin 4 (5-HT 4 ) receptors. The studies were performed at the Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet.

We evaluated the longitudinal stability of brain [ 18 F]altanserin PET measurements in elderly subjects and found stable 5-HT 2A receptors over two years and sufficient reproducibility and reliability to quantify the [ 18 F]altanserin binding. In addition, we found high intra- and interobserver stability.

The reproducibility of [ 11 C]SB207145 binding was evaluated in subjects scanned twice on the same day, and we validated the use of cerebellum as a reference region without specific 5-HT 4 receptor binding by scanning before and after administration of a 5-HT 4 receptor blocker. Quantitative kinetic models using arterial input data were compared to a non-invasive model, the simplified reference tissue model (SRTM) that uses the radiotracer uptake in cerebellum instead of arterial blood samples. We found that SRTM revealed high reproducibility and reliability and the blocking study supported the use of cerebellum as a reference region. By comparison with post mortem autoradiograpy for brain 5-HT 4 receptor binding, we found a high correlation of the spatial receptor distribution.

Further, we investigated the sensitivity of [ 11 C]SB207145 binding to competition from endogenous released serotonin and found that [ 11 C]SB207145 binding was unchanged and thus stable to acute fluctuations of the brain extracellular serotonin level.

In conclusion, an acceptable reproducibility and reliability in larger brain regions and a high intra- and interobserver stability lends [ 18 F]altanserin for use in longitudinal studies of elderly and patients with neuropsychiatric or neurodegenerative disorders. In vivo imaging of cerebral 5-HT 4 receptors can be reliably obtained in humans with [ 11 C]207145 PET either with arterial input or with non-invasive SRTM and is apparently insensitive to fluctuations in serotonin level.
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