Original article
Quantitative imaging of 5-HT1A receptor binding in healthy volunteers with [18f]p-MPPF

https://doi.org/10.1016/S0969-8051(00)00114-1Get rights and content

Abstract

Animal experiments have shown that 4-(2′-methoxyphenyl)-1-[2′-(N-2′′-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine ([18F]p-MPPF) can be used for 5-hydroxytryptamine1A (5-HT1A) receptor imaging. The aim of this study was to develop a method for the quantitative imaging of 5-HT1A receptors in healthy volunteers with [18F]p-MPPF. After injection of [18F]p-MPPF radioactivity was rapidly taken up in the brain, with the highest accumulation in the medial temporal cortex. Low levels of radioactivity were found in cerebellum and basal ganglia. Plasma clearance and metabolism of [18F]p-MPPF resulted in only about 1% of the radioactivity in plasma as parent radioligand after 10 min. Using a linear graphical method (Logan-Patlak), binding potentials were calculated in several brain areas. A good correlation (r = 0.95) was found between the obtained binding potentials and literature values for 5-HT1A receptor densities. A good correlation (r = 0.96) was also found between the body weight-corrected region/cerebellum ratios and the respective binding potentials. Moreover, a blocking experiment with pindolol (n = 3) showed a decrease of 40% in the region/cerebellum ratios of the target areas. Compared to those of [carbonyl-11C]WAY-100635, the binding potentials were four to six times lower, indicating that [18F]p-MPPF has a lower in vivo affinity for 5-HT1A receptors. In conclusion, [18F]p-MPPF can be used for the quantitative analysis of 5-HT1A receptor distribution in human brain.

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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