Design and Development of ^99mTc-Labeled FAPI Tracers for SPECT Imaging and ¹⁸⁸Re Therapy

Area of Science:

• Oncology
• Radiopharmaceuticals
• Molecular Imaging

Background:

• Epithelial tumors often recruit and activate fibroblasts into cancer-associated fibroblasts (CAFs), leading to overexpression of fibroblast-activating protein (FAP).
• DOTA-bearing FAP inhibitors (FAPIs) are effective for PET/CT imaging, but SPECT tracers offer a more accessible alternative.
• The radionuclide 188Re, chemically similar to 99mTc, can be used for FAP-targeted endoradiotherapy.

Purpose of the Study:

• To develop and evaluate 99mTc-labeled FAPIs as SPECT imaging agents for cancer diagnosis.
• To investigate the potential of these tracers for therapeutic applications using 188Re.
• To improve pharmacokinetic properties of initial FAPI candidates through chemical modification.

Main Methods:

• Preparation of 99mTc-tricarbonyl complexes using a versatile chelator for platform strategy.
• In vitro binding and competition assays on FAP-expressing cells (HT-1080-FAP, HEK-muFAP) and CD26-expressing cells (HEKCD26).
• In vivo characterization using planar scintigraphy and organ distribution studies in tumor-bearing mice.
• First-in-human SPECT imaging in patients with ovarian and pancreatic cancer.

Main Results:

• Initial 99mTc-FAPI-19 showed specific binding but poor pharmacokinetics (liver accumulation, biliary excretion, no tumor uptake) in mice.
• Modification with hydrophilic amino acids improved tracers, yielding excellent binding (>95% internalization), high affinity (6.4-12.7 nM), and significant tumor uptake (≤5.4% ID/g).
• The lead candidate, 99mTc-FAPI-34, demonstrated successful tumor accumulation in patients, correlating with PET/CT imaging (68Ga-FAPI-46).

Conclusions:

• 99mTc-FAPI-34 is a potent diagnostic tracer for SPECT imaging, particularly valuable where PET is unavailable.
• The developed chelator platform facilitates labeling with therapeutic radionuclides like 188Re for combined diagnostic and therapeutic applications.
• This approach offers a promising strategy for FAP-targeted cancer imaging and therapy.