Radiosynthesis and evaluation of a fluorine-18 radiotracer [¹⁸F]FS1P1 for imaging sphingosine-1-phosphate receptor 1

Abstract

Assessment of Sphingosine-1-phosphate receptor 1 (S1PR1) expression could be a unique tool to determine the neuroinflammatory status for central nervous system (CNS) disorders. Our preclinical results indicate that PET imaging...

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

“…In summary, out of these six F-18 radiotracers, [ 18 F]6h had the highest brain uptake. Compared to our leading S1PR1 radioligands, [ 18 F]6h has a higher brain uptake than the four-aromatic-ring [ 11 C]CS1P1 and its 18 F version, [ 18 F] FS1P1, as well as the three-aromatic-ring [ 18 F]TZ4877; it also has a more clinically favorable pharmacokinetics than [ 18 F] TZ4877 compared to [ 11 C]CS1P1 or [ 18 F]FS1P1 (Figure S1). The high initial brain uptake and slower brain washout pharmacokinetics combine the advantages of both parent radiotracers, [ 18 F]FS1P1 and [ 18 F]TZ4877, make [ 18 F]6h a more clinically favorable radiotracer which is worth transferring into human use.…”

“…Radiochemistry. To further evaluate these six leading candidates and identify the most promising S1PR1 radiotracer for imaging S1PR1 in the CNS, we next radiolabeled [ 18 F]8 with a good radiochemical yield (∼70%, decay corrected to the end of synthesis (EOS)). 18 Then, we used sodium borohydride to reduce [ 18 F]8 to afford the substituted benzyl alcohol [ 18 F]5a with a good radiochemical yield (∼52%), high chemical and radiochemical purity (>95%), and high molar activity (>57 GBq/ μmol (decay corrected to EOS).…”

“…The brain time− activity curve of each radiotracer was normalized to the standardized uptake value (SUV) and compared to each other. For the three CS1P1 derived F-18 radiotracers [ 18 F]5a−c, all three radiotracers showed a brain uptake (SUV) > 1.0 at 2 min post-injection, and then brain uptake gradually increased to SUVs of 1.40 for [ 18 F]5a, 1.49 for [ 18 F]5b, and 2.35 for [ 18 F] 5c at 120 min shown in Figure 3. The brain uptake of all three radiotracers continued to increase from 0 to 120 min and did not peak within 2 h, indicating these three radiotracers have slow brain uptake pharmacokinetics.…”

“…To continue our efforts on structural optimization of S1PR1 specific radiotracers for human use, we herein designed and synthesized 14 novel ligands through optimization of the structures of [ 18 F]FS1P1 and [ 18 F]TZ4877 by two strategies. First, the structures based on [ 18 F]FS1P1 kept the four-aromatic components of the original molecule and replaced the N-methylpropionic acid using different hydrophilic alkyl group(s) such as hydroxyl, Nmethylalkyl alcohol, aminoalkyl alcohol, and aminopropanoic acid. Second, the structures based on TZ4877 kept the three-aromatic components on the left and modified the right aromatic ring by introducing either halogen or methoxyl moieties at various positions, or replaced with different benzyl alcohols(s), N-methylalkyl acid(s) or N-methylalkyl alcohol at the end as hydrogen-donated group (Figure 2).…”

“…F]5b, ∼51 GBq/ μmol for [18 F]5c, decay corrected to EOS). The synthesis of [ 18 F]fluoroethoxyl-containing radiotracers [ 18 F]6a,f and [ 18 F]6h were accomplished using different strategies as shown in Scheme 4.…”