Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain

Abstract

Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [11C]CS1P1 into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound 6h is potent (IC50 = 8.7 nM) and selective for S1PR1. [18F]6h exhibited a high uptake in macaque brain (SUV > 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [18F]6h in vivo. Radiometabolite analysis confirmed no radiometabolite of [18F]6h entered into the brain to confound the PET measurement. In summary, [18F]6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.

Metabolite Study and Structural Authentication for the First-in-Human Use Sphingosine-1-phosphate Receptor 1 Radiotracer

“…Starting with 1-hydroxy-2,1-benzoxaborolane 5 reacted with methyl 4-bromo-3-(trifluoromethyl)­benzoate ( 6 ) by a Suzuki cross-coupling reaction, followed by hydrolysis using aqueous potassium hydroxide solution, the key intermediate benzoic acid 7 was obtained. Finally, cyclization of compounds 7 and amidoxime 8 afforded the desired benzyl alcohol containing compound 3 .…”

“…Positron emission tomography (PET) imaging of S1PR1 in humans provides a new methodology for the early detection and monitoring therapeutic efficacy. We reported several S1PR1-selective PET radioligands, , including [ 11 C] CS1P1 , − [ 18 F] FS1P1 , [ 18 F] TZ4877 , − and [ 18 F] TZ82112 , for imaging changes in S1PR1 expression in the brain (Figure ). [ 11 C] CS1P1 and [ 18 F] FS1P1 share the same molecular structure but are labeled at different positions with different isotopes.…”

PET Imaging of Sphingosine-1-Phosphate Receptor 1 with [18F]TZ4877 in Nonhuman Primates

“…This may be due to its poor brain penetration 33 , was ponesimod has an estimated logP of 4-4.5, or insu cient dosing, as administration of the targeted dose (0.1 mg/kg) was halted due to rapid drop in animal heart rate. Ponesimod was nonetheless selected for blocking because it presents a favorable safety pro le compared with other S1PR 1 inhibitors 34 and was previously shown to displace other S1PR 1 radiotracers 35 . Thus, performing PET imaging later after ponesimod dosing, or using a compound with better brain penetration (e.g., siponimod 36 , ngolimod 37 ), could provide improved evaluation of S1PR 1 blocking in future evaluation of S1PR 1 radiotracers, but must be balanced with animal safety concerns.…”

Design, synthesis, and biological evaluation of multiple F-18 S1PR1 radiotracers in rodent and nonhuman primate

“…1 and have identical binding properties and brain washout pharmacokinetics in nonhuman primates. 23 In addition, we also reported other potent 18 F-labeled S1PR1 radiotracers, including [ 18 F]TZ4877 [29][30][31][32][33] and [ 18 F]TZ82112, 34,35 contain a terminal alcohol as the hydrophilic head group (Fig. 1).…”

“…We previously reported that carboxylic acid-containing analogues showed good binding potency to S1PR1. 34 Therefore, we first explored the potency of new carboxylic acid-containing S1PR1 compounds 7a-e. As Next, we compared the impact of alcohols over carboxylic acids on binding potency. The alcohol-containing compounds 9a-i have binding potency like the corresponding carboxylic acid compounds.…”