99mTc-labeled FAPI compounds for cancer and inflammation: from radiochemistry to the first clinical applications

Abstract

Background: In recent years, fibroblast activating protein (FAP), a biomarker overexpressed by cancer-associated fibroblasts, has emerged as one of the most promising biomarkers in oncology. Similarly, FAP overexpression has been detected in various fibroblast-mediated inflammatory conditions such as liver cirrhosis and idiopathic pulmonary fibrosis. Along this trajectory, FAP-targeted positron emission tomography (PET), utilizing FAP inhibitors (FAPi) labeled with positron emitters, has gained traction as a powerful imaging approach in both cancer and inflammation. However, PET represents a high-cost technology, and its widespread adoption is still limited compared to the availability of gamma cameras. To address this issue, several efforts have been made to explore the potential of [^99mTc]Tc-FAPi tracers as molecular probes for imaging with gamma cameras and single photon emission computed tomography (SPECT).

Main body: Several approaches have been investigated for labeling FAPi-based compounds with ^99mTc. Specifically, the mono-oxo, tricarbonyl, isonitrile, and HYNIC strategies have been applied to produce [^99mTc]Tc-FAPi tracers, which have been tested in vitro and in animal models. Overall, these labeling approaches have demonstrated high efficiency and strong binding. The resulting [^99mTc]Tc-FAPi tracers have shown high specificity for FAP-positive cells and xenografts in both in vitro and animal model studies, respectively. However, the majority of [^99mTc]Tc-FAPi tracers have exhibited variable levels of lipophilicity, leading to preferential excretion through the hepatobiliary route and undesirable binding to lipoproteins. Consequently, efforts have been made to synthesize more hydrophilic FAPi-based compounds to improve pharmacokinetic properties and achieve a more favorable biodistribution, particularly in the abdominal region. SPECT imaging with [^99mTc]Tc-FAPi has yielded promising results in patients with gastrointestinal tumors, demonstrating comparable or superior diagnostic performance compared to other imaging modalities. Similarly, encouraging outcomes have been observed in subjects with gliomas, lung cancer, breast cancer, and cervical cancer. Beyond oncological applications, [^99mTc]Tc-FAPi-based imaging has been successfully employed in myocardial and idiopathic pulmonary fibrosis.

Conclusions: This overview focuses on the various radiochemical strategies for obtaining [^99mTc]Tc-FAPi tracers, highlighting the main challenges encountered and possible solutions when applying each distinct approach. Additionally, it covers the preclinical and initial clinical applications of [^99mTc]Tc-FAPi in cancer and inflammation.

Keywords: Fibroblast activation protein; Inflammation; Molecular imaging; Oncology; PET; SPECT.

Fig. 1

Some examples of bioactive molecule associated to different technetium-99m cores: a, di-oxo TcO₂⁺ core; b, mono-oxo TcO⁺ core; c, Tc-HYNIC core; d, Tc(CO)₃⁺ core

Fig. 2

Schematic representation of the labeling of a bioactive molecule using the [Tc(N)(PNP)]²⁺approach to give the [^99mTc][Tc(N)PNP-Cys-biomolecule]^0/+ complex

Fig. 3

Schematic representation of the bioactive molecules labeling using: a, the ^99mTc “4 + 1” approach; b, bifunctional monodentate isonitrile ligands to give the [^99mTc][Tc(I)(CN-biomolecule)₆]⁺ complex

Fig. 4

Chemical structure of ^99mTc-tricarbonyl-FAPI complexes

Fig. 5

The figure shows the direct comparison of the uptake at [^99mTc]Tc-HFAPi SPECT/CT (left) and immunohistochemistry staining (right) in primary digestive-tract tumors. The last case (P4) refers to a highly differentiated rectal adenocarcinoma tumor that resulted false negative at [^99mTc]Tc-HFAPi SPECT/CT. Scale bar, 200 μm; T: pri- mary tumour; NT: Tumour-adjacent tissue. Reprinted from (Jia et al., 2023), under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). No changes were made

Fig. 6

Serial whole-body scans acquired in a representative patient affected by idiopathic pulmonary fibrosis at different time-points. Note the physiological distribution of the tracer in the liver, intestinal tract, pancreas, gallbladder and spleen and the pathological uptake in both the lungs. Reprinted from (Liu et al. 2023b), under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). No changes were made

Fig. 7

Fused axial SPECT/CT images in a patient affected by idiopathic pulmonary fibrosis. Upper row: corresponding emissive A, fused B and transmissive C slices of the lower left and right pulmonary lobes; note the intense tracer incorporation. Lower row: lower tracer incorporation can be observed in the corresponding emissive D, fused E and transmissive F slices of the middle-upper region of the lungs. Reprinted from (Liu et al. 2023b), under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). No changes were made