Characterization of the serotonin 2A receptor selective PET tracer (R)-[18F]MH.MZ in the human brain
The serotonin receptor subtype 2A antagonist (5-HT2AR) (R)-[18F]MH.MZ has in preclinical studies been identified as a promising PET imaging agent for quantification of cerebral 5-HT2ARs. It displays a very similar selectivity profile as [11C]MDL 100907, one of the most selective compounds identified thus far for the 5-HT2AR. 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-HT2AR 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-HT2AR in the human brain in vivo.
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-HT2AR binding, and performance of different kinetic modeling approaches.
Highest uptake was determined in 5-HT2AR rich regions with a BPND 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-HT2AR and could be blocked by pretreatment with ketanserin. Moreover, outcomes measures were stable after 100–110 min.
(R)-[18F]MH.MZ is a suitable PET tracer to image and quantify the 5-HT2AR 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-HT2AR system.
Keywords[18F]MH.MZ MDL 100907 5-HT2A receptor Positron emission tomography (PET) Kinetic modeling
The authors would like to thank Dr. Geoff Warnock from PMod Technologies, Switzerland, for his input regarding blood sampling and data evaluation as well as Dr. Evelyng Faure Lobos for acquiring the MRI scans at the Imaging Department of FALP (Instituto Oncológico Fundación Arturo López Pérez), Santiago de Chile, Chile. We also thank Carlos Elgueta and Dr. Mario Avila from Positronpharma for the assistance in tracer production and Irene Coudeu and Ana Hurtado for their help with technical issues.
This study was in part funded by the Savværksejer Jeppe Juhls og Hustru Ovita Juhls foundation.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Comité Ético Cientifico, Servicio de Salud Metropolitano Oriente, permits 20150407 and 20170307) and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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