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![An Automated Radiosynthesis of [68Ga]Ga-FAPI-46 for Routine Clinical Use](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F66708.jpg&w=3840&q=50)
An Automated Radiosynthesis of [68Ga]Ga-FAPI-46 for Routine Clinical Use
Published on: May 24, 2024
Design and preclinical evaluation of 99mTc-Labeled dimer FAPI-46 derivatives as potential tumor radiotracers
Qing Ruan1, Lina Diao2, Zuojie Li2
1Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing, 100875, PR China; Key Laboratory of Beam Technology of the Ministry of Education, School of Physics and Astronomy, Beijing Normal University, Beijing, 100875, PR China.
Abstract:
Fibroblast activation protein (FAP) is a crucial target for tumor diagnosis and treatment. FAP inhibitors (FAPIs) can selectively bind to FAP, and ligands with multiple targeting groups are anticipated to improve tumor-specific uptake. A dimeric FAPI ligand (L2) with high affinity for FAP was selected. Four hydrophilic 99mTc-labeled complexes ([99mTc]Tc-L2-TPPTS, [99mTc]Tc-L2-TPPMS, [99mTc]Tc-L2-PDA, and [99mTc]Tc-L2-NIC) were successfully prepared and exhibited good stability in vitro. Among them, [99mTc]Tc-L2-TPPTS and [99mTc]Tc-L2-PDA showed superior cellular uptake and specific binding to FAP. They displayed minimal nontarget uptake in normal mice and exhibited significant tumor uptake (22.01 ± 1.38 % ID/g and 26.58 ± 2.17 % ID/g at 1 h post-injection) with high specificity for FAP in U87MG tumor-bearing mice. SPECT/CT imaging experiments revealed specific accumulation of both complexes at the U87MG, PANC-1, and HT-1080-FAP tumor sites, suggesting their excellent specificity for FAP. In particular, [99mTc]Tc-L2-TPPTS has lower nontarget uptake in various tumor models and accelerated blood clearance. Additionally, an L2-TPPTS kit was successfully prepared providing convenient conditions for subsequent clinical transformation research.
Insights
New technetium-99m labeled fibroblast activation protein inhibitors (FAPIs) show high tumor uptake and specificity. The L2-TPPTS complex demonstrates excellent potential for FAP-targeted cancer imaging and therapy.
Area of Science:
- Radiochemistry
- Nuclear Medicine
- Oncology
Background:
- Fibroblast activation protein (FAP) is a key biomarker for cancer diagnosis and therapy.
- Developing targeted agents that selectively bind FAP can enhance tumor visualization and treatment efficacy.
- Multivalent ligands are explored to improve tumor-specific uptake of imaging agents.
Purpose of the Study:
- To synthesize and evaluate novel 99mTc-labeled dimeric FAPI ligands for improved tumor targeting.
- To assess the in vitro and in vivo performance of these FAP-targeted radiotracers.
- To investigate the potential of L2-TPPTS as a clinical candidate for FAP-targeted imaging.
Main Methods:
- Synthesis and characterization of four 99mTc-labeled dimeric FAPI complexes ([99mTc]Tc-L2-TPPTS, [99mTc]Tc-L2-TPPMS, [99mTc]Tc-L2-PDA, [99mTc]Tc-L2-NIC).
- In vitro stability and cellular uptake studies.
- In vivo biodistribution and SPECT/CT imaging in tumor-bearing mouse models (U87MG, PANC-1, HT-1080-FAP).
- Preparation of a convenient kit formulation for L2-TPPTS.
Main Results:
- All four 99mTc-labeled complexes were successfully prepared with good in vitro stability.
- [99mTc]Tc-L2-TPPTS and [99mTc]Tc-L2-PDA exhibited superior cellular uptake and specific FAP binding.
- These agents showed minimal non-target uptake in normal mice and significant tumor uptake in U87MG-bearing mice.
- SPECT/CT imaging confirmed specific tumor accumulation in various FAP-positive tumor models.
- [99mTc]Tc-L2-TPPTS demonstrated lower non-target uptake and faster blood clearance compared to other analogs.
- A stable L2-TPPTS kit was developed for potential clinical translation.
Conclusions:
- The novel 99mTc-labeled dimeric FAPI ligands, particularly [99mTc]Tc-L2-TPPTS, show high affinity and specificity for FAP.
- These radiotracers are promising for accurate FAP-targeted cancer diagnosis and potentially therapy.
- [99mTc]Tc-L2-TPPTS is a strong candidate for further clinical development due to its favorable pharmacokinetic profile.
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