Original articleQuantitative imaging of 5-HT1A receptor binding in healthy volunteers with [18f]p-MPPF
Introduction
It has been established that the serotonin1A (5-HT1A) receptor plays an important role in a variety of psychiatric and neurodegenerative diseases 2, 3, 5, 18, 24. Although in vitro autoradiography studies have reported changes in receptor density in schizophrenia, depression, and dementia 6, 9, 14, 20, 21, the relation between postmortem receptor density and in vivo functionality is still unclear.
Positron emission tomography (PET) has the unique ability to visualize biological processes in a noninvasive, quantitative manner. With a suitable radioligand, it may be possible to measure differences in receptor density between patients and age-matched healthy volunteers, or the response of the 5-HT1A receptor population in patients upon treatment. One of the radioligands that has been developed for the imaging of 5-HT1A receptors is 4-(2′-methoxyphenyl)-1-[2′-(N-2′′-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine ([18F]p-MPPF) 19, 23. Animal experiments have shown that [18F]p-MPPF displays a regional radioactivity uptake in good correlation with known receptor distribution and density 12, 16, 19. Moreover, the uptake can be blocked with the selective 5-HT1A antagonist, WAY-100635, and with the selective 5-HT1A agonists, 8-OH DPAT and NAN-190 12, 16, 19. These results indicate that [18F]p-MPPF might be a useful radiopharmaceutical for human studies. The aim of this research was to determine if the binding of [18F]p-MPPF to the 5-HT1A receptor in healthy volunteers can be analyzed in a quantitative manner using a linear graphical method (Logan-Patlak: 11, 13), and if this uptake can be reduced by the administration of the 5-HT1A antagonist pindolol 1, 15.
Section snippets
Volunteers
The study was approved by the medical ethics committee of the Groningen University Hospital. Six subjects (two male, four female; age range 21–65 years) were included after written informed consent had been obtained and an independent physician had confirmed their suitability to take part in the study.
Radiochemistry
[18F]p-MPPF was prepared by nucleophilic substitution of the aromatic nitro group [unpublished data, for comparable methods see 12, 19]. Quality control was performed by means of reverse phase
Results
Injected [18F]p-MPPF was rapidly cleared from plasma and rapidly metabolized (Fig. 1). After 10 minutes, only 1% of the injected radioactivity in plasma represented parent compound. Analysis of [18F]p-MPPF-derived radioactivity in plasma by means of reverse phase HPLC showed only one radioactive metabolite with a retention time of 3 min. A large fraction of injected [18F]p-MPPF (approximately 89%) was bound to plasma proteins. The radiolabeled metabolites of [18F]p-MPPF showed less protein
Discussion
Even though only low amounts of [18F]p-MPPF were injected in this preliminary human study (70 ± 18 MBq), it was clear from the images obtained that [18F]p-MPPF showed a regional distribution that corresponds to the known 5-HT1A receptor localization (Fig. 2A) 4, 17. Moreover, the binding potentials calculated from several ROIs using the metabolite-corrected arterial plasma curve as input function and the cerebellum as reference tissue were in good correlation with previous PET studies using [
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2012, Nuclear Medicine and BiologyCitation Excerpt :Taking this into consideration, studies have been directed toward 18F-labeled analogues of WAY-100635 (Fig. 1). The 5-HT1A antagonist [18F]MPPF was found to be prepared easily, selective and with high affinity for the 5-HT1A receptor, but lower than WAY-100635 [15]. Pre-treatment with non-labeled WAY-100635 showed only 60% reduction of brain uptake [16].
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