Molecular imaging and biology · 2025
PET Imaging of Sphingosine-1-Phosphate Receptor 1 with [18F]TZ4877 in Nonhuman Primates.
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Gu Jiwei, Zheng Ming-Qiang, Holden Daniel, Fowles Krista, Qiu Lin, Felchner Zachary, Zhang Li, Ropchan Jim, Gropler Robert J, Carson Richard E, Tu Zhude, Huang Yiyun, Hillmer Ansel T
Аннотация
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 reproducible 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.
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 reproducible 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.