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

Qiu, Lang; Jiang, Hao; Zhou, Chunlin; Wang, Jinzhi; Yu, Yanbo; Zhao, Haiyang; Huang, Tianyu; Gropler, Robert J.; Perlmutter, Joel S.; Benzinger, Tammie L.S.

doi:10.1021/acs.jmedchem.2c01752

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…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 .…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Qiu,

Jiang,

Cho

et al. 2024

ACS Chem. Neurosci.

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The sphingosine-1-phosphate receptor 1 (S1PR1) radiotracer [ 11 C]CS1P1 has shown promise in proof-of-concept PET imaging of neuroinflammation in multiple sclerosis (MS). Our HPLC radiometabolite analysis of human plasma samples collected during PET scans with [ 11 C]CS1P1 detected a radiometabolite peak that is more lipophilic than [ 11 C]CS1P1. Radiolabeled metabolites that cross the blood-brain barrier complicate quantitative modeling of neuroimaging tracers; thus, characterizing such radiometabolites is important. Here, we report our detailed investigation of the metabolite profile of [ 11 C]CS1P1 in rats, nonhuman primates, and humans. CS1P1 is a fluorine-containing ligand that we labeled with C-11 or F-18 for preclinical studies; the brain uptake was similar for both radiotracers. The same lipophilic radiometabolite found in human studies also was observed in plasma samples of rats and NHPs for CS1P1 labeled with either C-11 or F-18. We characterized the metabolite in detail using rats after injection of the nonradioactive CS1P1. To authenticate the molecular structure of this radiometabolite, we injected rats with 8 mg/kg of CS1P1 to collect plasma for solvent extraction and HPLC injection, followed by LC/MS analysis of the same metabolite. The LC/MS data indicated in vivo mono-oxidation of CS1P1 produces the metabolite. Subsequently, we synthesized three different mono-oxidized derivatives of CS1P1 for further investigation. Comparing the retention times of the mono-oxidized derivatives with the metabolite observed in rats injected with CS1P1 identified the metabolite as N-oxide 1, also named TZ82121. The MS fragmentation pattern of N-oxide 1 also matched that of the major metabolite in rat plasma. To confirm that metabolite TZ82121 does not enter the brain, we radiosynthesized [ 18 F]TZ82121 by the oxidation of [ 18 F]FS1P1. Radio-HPLC analysis confirmed that [ 18 F]TZ82121 matched the radiometabolite observed in rat plasma post injection of [ 18 F] FS1P1. Furthermore, the acute biodistribution study in SD rats and PET brain imaging in a nonhuman primate showed that [ 18 F] TZ82121 does not enter the rat or nonhuman primate brain. Consequently, we concluded that the major lipophilic radiometabolite N-oxide [ 11 C]TZ82121, detected in human plasma post injection of [ 11 C]CS1P1, does not enter the brain to confound quantitative PET data analysis. [ 11 C]CS1P1 is a promising S1PR1 radiotracer for detecting S1PR1 expression in the CNS.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Qiu,

Jiang,

Cho

et al. 2024

ACS Chem. Neurosci.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Gu,

Zheng,

Holden

et al. 2024

Preprint

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Purpose The sphingosine-1-phosphate receptor-1 (S1PR1) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR1-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR1 radiotracer, [18F]TZ4877, in nonhuman primates. Procedures: [18F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[18F]/F− followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120–180 min following bolus injection of 118–163 MBq [18F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction (fP). Each animal was scanned at baseline, 15–18 min after 0.047–0.063 mg/kg of the S1PR1 inhibitor ponesimod, 33 min after 0.4–0.8 mg/kg of the S1PR1-specific compound TZ82112, and 167–195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume (VT/fP). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA. Results [18F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [18F]TZ4877 fP was low (< 1%), and [18F]TZ4877 VT/fP values were 233–866 mL/cm3. TZ82112 dose-dependently reduced [18F]TZ4877 VT/fP, while ponesimod and endotoxin exhibited negligible effects on VT/fP, possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate. Conclusions [18F]TZ4877 exhibits reversible kinetic properties, but the low fP value limits quantification with this radiotracer. S1PR1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.

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Synthesis, radiosynthesis and biochemical evaluation of fluorinated analogues of sphingosine-1-phosphate receptor 3 specific antagonists using PET

Prasad,

Wagner,

Keul

et al. 2024

Bioorganic & Medicinal Chemistry

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

Cited by 4 publications

References 48 publications

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

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

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

Synthesis, radiosynthesis and biochemical evaluation of fluorinated analogues of sphingosine-1-phosphate receptor 3 specific antagonists using PET

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