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.

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

期刊论文
发表日期：

2025年1月8日

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Jiwei Gu,
Ming-Qiang Zheng,
Daniel Holden,
Krista Fowles,
Lin Qiu,
Zachary Felchner,
Li Zhang,
Jim Ropchan,
Robert J. Gropler,
Richard E. Carson,
Zhude Tu,
Yiyun Huang,
Ansel T. Hillmer

摘要

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 (f_P). 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 (V_T/f_P). 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 f_P was low (<1%), and [¹⁸F]TZ4877 V_T/f_P values were 233-866 mL/cm³. TZ82112 dose-dependently reduced [¹⁸F]TZ4877 V_T/f_P, while ponesimod and endotoxin exhibited negligible effects on V_T/f_P, 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 f_P 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.

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

摘要

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