Synthesis and evaluation of ¹⁸F-labeled 5-HT_2A receptor agonists as PET ligands

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• 作者：Matthias M. Herth^a ; ^b ; ^c ; ¹ ; Ida Nymann Petersen^a ; ¹ ; Hanne Demant Hansen^b ; Martin Hansen^a ; Anders Ettrup^b ; Anders A. Jensen^a ; Szabolcs Lehel^c ; Agnete Dyssegaard^b ; Nic Gillings^c ; Gitte M. Knudsen^b ; Jesper L. Kristensen^a ; ^{jesper.kristensen@sund.ku.dk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PET ; Fluorine-18 ; 5-HT2AR ; Agonist ; Cimbi-36
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：43
• 期：8
• 页码：455-462
• 全文大小：646 K

文摘

The serotonin 2A receptor (5-HT_2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT_2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT_2AR agonist PET tracer, [¹¹C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an ¹⁸F-labeled 5-HT_2AR agonist PET-ligand.

Methods and results

Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT_2A agonists. ¹⁸F-labeling of the appropriate precursors was performed using [¹⁸F]FETos, typically yielding 0.2–2.0 GBq and specific activities of 40–120 GBq/μmol. PET studies in Danish landrace pigs revealed that [¹⁸F]1 displayed brain uptake in 5-HT_2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT_2AR selective antagonist. [¹⁸F]2 and [¹⁸F]3 showed very low brain uptake.

Conclusion

None of the investigated ¹⁸F-labeled Cimbi-36 derivatives [¹⁸F]1, [¹⁸F]2 and [¹⁸F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT_2AR. Although for [¹⁸F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT_2AR antagonist.