Purpose Fibroblast activation protein (FAP) has emerged as one of the most promising theranostic targets. FT-FAPI, a potential FAP-targeted probe with enhanced tumor-targeting ability using an organotrifluoroborate linker, was verified for the biological effect in cell and animal experiments in previous work. However, the differences in pharmacokinetic profiles, biodistribution and dosimetry of FT-FAPI under multiple nuclides labeling in animals and humans is unclear. In this study, we sought to explore the discrepancies in the performance of FT-FAPI after labeling with different radioisotopes and to compare 68Ga-FT-FAPI with 68Ga-FAPI-04 in healthy volunteers. Methods Preparation and quality control of 18F-/68Ga-/177Lu-FT-FAPI injections were conducted. Biodistribution studies were performed in mice and pharmacokinetic analysis were performed using blood samples. 18F-FT-FAPI and 68Ga-FT-FAPI were initially tested in normal volunteers, respectively. Further, 68Ga-FT-FAPI was scanned at multiple time points for 1 h dynamic, 2 h and 3 h static imaging, and compared with 68Ga-FAPI-04 to clarify the distribution patterns and excretion parameters. Radiation dosimetry was estimated based on the uptake of the probes in organs of mice or humans, respectively. Results 18F-/68Ga-/177Lu-FT-FAPI showed high safety and tolerability in mice or humans. The pharmacokinetic characteristics of FT-FAPI in mice and humans best fit a two-compartment model. In mice, the results of biodistribution showed that the clearance half-life (T1/2β) of FT-FAPI varied with different labeled radionuclides, with 68Ga-FT-FAPI having the shortest T1/2β of 26.1 min. In HT-1080-FAP tumor-bearing mice, 177Lu-FT-FAPI showed higher tumor uptake and longer retention time than 177Lu-FAPI-04, which implies a higher radiation dose in the tumor. In healthy volunteers, both 18F-FAPI-04 and 68Ga-FT-FAPI were metabolized by the kidneys and excreted through the urinary system. The uptake of 68Ga-FT-FAPI in most normal tissues was similar to that of 68Ga-FAPI-04, being higher only in the sublingual gland, thyroid gland and pancreas. 68Ga-FT-FAPI had similar T1/2β (75.0 min vs. 77.2 min) and a slightly higher effective dose (ED) (12.4 ± 1.51 µSv·MBq−1 vs. 9.99 ± 1.85 µSv·MBq−1) compared to 68Ga-FAPI-04. Compared to 68Ga-FT-FAPI, 18F-FT-FAPI has slightly higher liver and bone uptake, especially in the delayed time points. Conclusion The pharmacokinetics of FT-FPAI varies depending on the labeled nuclide. Compared to 177Lu-FAPI-04, 177Lu-FT-FAPI showed higher tumor uptake and longer retention time. In healthy volunteers, 68Ga-FT-FAPI had lower renal uptake and higher sublingual gland, thyroid gland and pancreas uptake at 1 h p.i. than that of 68Ga-FAPI-04, with no significant differences in other organs. Further optimization will be conducted for the radiolabeling process of 18F-FT-FAPI to evaluate its diagnostic efficacy.

Pharmacokinetics study of FT-FAPI, a novel multi-nuclide label-able FAP targeting tracer, in mice and healthy volunteers

期刊论文
发表日期：

2025年5月27日

查看全文

Jiajun Ye,
Shu Yang,
Yu Liu,
Zhiyong Quan,
Mingru Zhang,
Guiyu Li,
Zifan Zhu,
Jia Wang,
Taoqi Ma,
Junlin Wang,
Zhibo Liu,
Jing Wang,
Fei Kang

摘要

Purpose

Fibroblast activation protein (FAP) has emerged as one of the most promising theranostic targets. FT-FAPI, a potential FAP-targeted probe with enhanced tumor-targeting ability using an organotrifluoroborate linker, was verified for the biological effect in cell and animal experiments in previous work. However, the differences in pharmacokinetic profiles, biodistribution and dosimetry of FT-FAPI under multiple nuclides labeling in animals and humans is unclear. In this study, we sought to explore the discrepancies in the performance of FT-FAPI after labeling with different radioisotopes and to compare ⁶⁸Ga-FT-FAPI with ⁶⁸Ga-FAPI-04 in healthy volunteers.

Methods

Preparation and quality control of ¹⁸F-/⁶⁸Ga-/¹⁷⁷Lu-FT-FAPI injections were conducted. Biodistribution studies were performed in mice and pharmacokinetic analysis were performed using blood samples. ¹⁸F-FT-FAPI and ⁶⁸Ga-FT-FAPI were initially tested in normal volunteers, respectively. Further, ⁶⁸Ga-FT-FAPI was scanned at multiple time points for 1 h dynamic, 2 h and 3 h static imaging, and compared with ⁶⁸Ga-FAPI-04 to clarify the distribution patterns and excretion parameters. Radiation dosimetry was estimated based on the uptake of the probes in organs of mice or humans, respectively.

Results

¹⁸F-/⁶⁸Ga-/¹⁷⁷Lu-FT-FAPI showed high safety and tolerability in mice or humans. The pharmacokinetic characteristics of FT-FAPI in mice and humans best fit a two-compartment model. In mice, the results of biodistribution showed that the clearance half-life (T_1/2β) of FT-FAPI varied with different labeled radionuclides, with ⁶⁸Ga-FT-FAPI having the shortest T_1/2β of 26.1 min. In HT-1080-FAP tumor-bearing mice, ¹⁷⁷Lu-FT-FAPI showed higher tumor uptake and longer retention time than ¹⁷⁷Lu-FAPI-04, which implies a higher radiation dose in the tumor. In healthy volunteers, both ¹⁸F-FAPI-04 and ⁶⁸Ga-FT-FAPI were metabolized by the kidneys and excreted through the urinary system. The uptake of ⁶⁸Ga-FT-FAPI in most normal tissues was similar to that of ⁶⁸Ga-FAPI-04, being higher only in the sublingual gland, thyroid gland and pancreas. ⁶⁸Ga-FT-FAPI had similar T_1/2β (75.0 min vs. 77.2 min) and a slightly higher effective dose (ED) (12.4 ± 1.51 µSv·MBq⁻¹ vs. 9.99 ± 1.85 µSv·MBq⁻¹) compared to ⁶⁸Ga-FAPI-04. Compared to ⁶⁸Ga-FT-FAPI, ¹⁸F-FT-FAPI has slightly higher liver and bone uptake, especially in the delayed time points.

Conclusion

The pharmacokinetics of FT-FPAI varies depending on the labeled nuclide. Compared to ¹⁷⁷Lu-FAPI-04, ¹⁷⁷Lu-FT-FAPI showed higher tumor uptake and longer retention time. In healthy volunteers, ⁶⁸Ga-FT-FAPI had lower renal uptake and higher sublingual gland, thyroid gland and pancreas uptake at 1 h p.i. than that of ⁶⁸Ga-FAPI-04, with no significant differences in other organs. Further optimization will be conducted for the radiolabeling process of ¹⁸F-FT-FAPI to evaluate its diagnostic efficacy.