Characterization of the serotonin 2A receptor selective PET tracer (R)-[18F]MH.MZ in the human brain

Vasko Kramer; Agnete Dyssegaard; Jonathan Flores; Cristian Soza-Ried; Frank Rösch; Gitte Moos Knudsen; Horacio Amaral; Matthias M Herth

doi:10.1007/s00259-019-04527-w

Characterization of the serotonin 2A receptor selective PET tracer (R)-[¹⁸F]MH.MZ in the human brain

Eur J Nucl Med Mol Imaging. 2020 Feb;47(2):355-365. doi: 10.1007/s00259-019-04527-w. Epub 2019 Oct 12.

Authors

Vasko Kramer^{1

2}, Agnete Dyssegaard³, Jonathan Flores⁴, Cristian Soza-Ried⁴, Frank Rösch⁵, Gitte Moos Knudsen³, Horacio Amaral^{4

6}, Matthias M Herth^{7

8}

Affiliations

¹ Center for Nuclear Medicine & PET/CT Positronmed, Providencia, 7501068, Santiago, Chile. vkramer@positronpharma.cl.
² Positronpharma SA, Providencia, 7500921, Santiago, Chile. vkramer@positronpharma.cl.
³ Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
⁴ Center for Nuclear Medicine & PET/CT Positronmed, Providencia, 7501068, Santiago, Chile.
⁵ Institute of Nuclear Chemistry, Johannes Gutenberg-University, Fritz-Strassmann-Weg 2, 55128, Mainz, Germany.
⁶ Positronpharma SA, Providencia, 7500921, Santiago, Chile.
⁷ Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark. matthias.herth@sund.ku.dk.
⁸ Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. matthias.herth@sund.ku.dk.

PMID: 31606832
DOI: 10.1007/s00259-019-04527-w

Abstract

Purpose: The serotonin receptor subtype 2A antagonist (5-HT_2AR) (R)-[¹⁸F]MH.MZ has in preclinical studies been identified as a promising PET imaging agent for quantification of cerebral 5-HT_2ARs. It displays a very similar selectivity profile as [¹¹C]MDL 100907, one of the most selective compounds identified thus far for the 5-HT_2AR. As [¹¹C]MDL 100907, (R)-[¹⁸F]MH.MZ also displays slow brain kinetics in various animal models; however, the half-life of fluorine-18 allows for long scan times and consequently, a more precise determination of 5-HT_2AR binding could still be feasible. In this study, we aimed to evaluate the potential of (R)-[¹⁸F]MH.MZ PET to image and quantify the 5-HT_2AR in the human brain in vivo.

Methods: Nine healthy volunteers underwent (R)-[¹⁸F]MH.MZ PET at baseline and four out of these also received a second PET scan, after ketanserin pretreatment. Regional time-activity curves of 17 brain regions were analyzed before and after pretreatment. We also investigated radiometabolism, time-dependent stability of outcomes measures, specificity of (R)-[¹⁸F]MH.MZ 5-HT_2AR binding, and performance of different kinetic modeling approaches.

Results: Highest uptake was determined in 5-HT_2AR rich regions with a BP_ND of approximately 1.5 in cortex regions. No radiometabolism was observed. 1TCM and 2TCM resulted in similar outcome measure, whereas reference tissue models resulted in a small, but predictable bias. (R)-[¹⁸F]MH.MZ binding conformed to the known distribution of 5-HT_2AR and could be blocked by pretreatment with ketanserin. Moreover, outcomes measures were stable after 100-110 min.

Conclusion: (R)-[¹⁸F]MH.MZ is a suitable PET tracer to image and quantify the 5-HT_2AR system in humans. In comparison with [¹¹C]MDL 100907, faster and more precise outcome measure could be obtained using (R)-[¹⁸F]MH.MZ. We believe that (R)-[¹⁸F]MH.MZ has the potential to become the antagonist radiotracer of choice to investigate the human 5-HT_2AR system.

Keywords: 5-HT2A receptor; Kinetic modeling; MDL 100907; Positron emission tomography (PET); [18F]MH.MZ.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biological Transport
Brain / diagnostic imaging
Humans
Kinetics
Positron-Emission Tomography*
Receptor, Serotonin, 5-HT2A*

Substances

Receptor, Serotonin, 5-HT2A