A Potential PET Radiotracer for the 5-HT_2C Receptor: Synthesis and in Vivo Evaluation of 4-(3-[¹⁸F]fluorophenethoxy)pyrimidine

Abstract

The serotonin 2C receptor subtype (5-HT) is an excitatory 5-HT receptor widely distributed throughout the central nervous system. As the 5-HT receptor displays multiple actions on various neurotransmitter systems including glutamate, dopamine, epinephrine, and γ-aminobutyric acid (GABA), abnormalities of the 5-HT receptor are associated with psychiatric diseases such as depression, schizophrenia, drug abuse, and anxiety. Up to date, three kinds of 5-HT PET radiotracers such as [C]N-methylated arylazepine (1), [C]WAY-163909 (2), and [F]fluorophenylcyclopropane (3) have been developed, but they may not be suitable for in vivo 5-HT imaging study due to their modest specific binding. Herein, the synthesis and in vivo evaluation of 4-(3-[F]fluorophenethoxy)pyrimidine [F]4 as a potential PET radiotracer for the 5-HT receptor is described. [F]4 was synthesized by nucleophilic aromatic substitution of diaryliodonium precursor 17a with a 7.8 ± 2.7% (n = 6, decay corrected) radiochemical yield and over 99% radiochemical purity, showing an 89 ± 14 GBq/μmol specific radioactivity. The in vivo PET imaging studies of [F]4 with or without lorcaserin, a U.S. Food and Drug Administration approved selective 5-HT agonist, demonstrated that [F]4 exhibits a high level of specific binding to 5-HT receptors in the rat brain.

Metabolic Imaging and Biological Assessment: Platforms to Evaluate Acute Lung Injury and Inflammation

“…Future development for PET imaging can entail development of other substrates, similar to what was discussed earlier, to more specifically characterize the type of inflammation in the tissue. Moreover, additional novel tracers that are functionalized ligands that can bind to specific receptors may be synthesized to provide additional insight into the immune-pathogenesis of the disease ( Kim et al, 2017 ).…”

Innovative Clinical Trial Designs for Precision Medicine in Heart Failure with Preserved Ejection Fraction

“…Figure 4 presents a hypothetical example of such an approach using the weight loss drug lorcaserin, a serotonin receptor subtype (5-HT 2c ) agonist [43,44]. Morbidly obese patients with evidence of unoccupied 5-HT 2c receptors (which, in the future, could be quantified using positron emission tomography-computed tomograph [PET-CT] scanning of the brain [45], Figure 4 [top panel]) and one of the aforementioned obesity-related conditions would be enrolled in the trial in a basket design (Figure 4, bottom panel) with a variety of endpoints.…”

“…Top panel PET-CT images reproduced from Ref. #45 (under the open access American Chemical Society AuthorChoice License).…”

Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators

“…Recently, pyrimidine analogue 3 with good pharmacological and pharmacokinetic properties has been reported as a potential 5-HT 2C agonist [ 22 ]. Our in vitro study of this molecule proved that it has a high potency against the 5-HT 2C receptor and relative good selectivity against the 5-HT 2A receptor [ 23 ]. However, the binding affinity of 3 to the 5-HT 2B receptor is still too high, which prompted us to investigate this compound for the development of 5-HT 2C selective agonists.…”