[99mTc]Tc-iFAP Radioligand for SPECT/CT Imaging of the Tumor Microenvironment: Kinetics, Radiation Dosimetry, and Imaging in Patients

Abstract

Tumor microenvironment fibroblasts overexpress the fibroblast activation protein (FAP). We recently reported the preclinical evaluation of [99mTc]Tc-iFAP as a new SPECT radioligand capable of detecting FAP. This research aimed to evaluate the kinetic and dosimetric profile of [99mTc]Tc-iFAP in healthy volunteers, and to assess the radioligand uptake by different solid tumors in three cancer patients. [99mTc]Tc-iFAP was obtained from lyophilized formulations prepared under GMP conditions with >98% radiochemical purity. Whole-body scans of six healthy subjects were obtained at 0.5, 2, 4, and 24 h after [99mTc]Tc-iFAP (740 MBq) administration. A 2D-planar/3D-SPECT hybrid activity quantitation method was used to fit the biokinetic models of the source organs (volume of interest: VOI) as exponential functions (A(t)VOI). The total nuclear transformations (N) that occurred in the source organs were calculated from the mathematical integration (0,∞) of A(t)VOI. The OLINDA code was used to estimate the radiation doses. Three treatment-naive patients (breast, lung, and cervical cancer) with a prior [18F]FDG PET/CT scan underwent whole-body, chest, and abdominal SPECT/CT scanning after [99mTc]Tc-iFAP (740 MBq) administration. Both imaging methods were compared visually and quantitatively. Oncological diagnoses were performed histopathologically. The results showed favorable [99mTc]Tc-iFAP biodistribution and kinetics due to rapid blood activity removal (t1/2α = 2.22 min and t1/2β = 90 min) and mainly renal clearance. The mean radiation equivalent doses were 5.2 ± 0.8 mSv for the kidney and 1.7 ± 0.3 mSv for the liver after administration of 740 MBq. The effective dose was 2.3 ± 0.4 mSv/740 MBq. [99mTc]Tc-iFAP demonstrated high and reliable uptake in the primary tumor lesions and lymph node metastases in patients with breast, cervical, and lung cancer, which correlated with that detected by [18F]FDG PET/CT. The tumor microenvironment molecular imaging from cancer patients obtained in this research validates the performance of additional clinical studies to determine the utility of [99mTc]Tc-iFAP in the diagnosis and prognosis of different types of solid tumors.

[99mTc]Tc-iFAP/SPECT Tumor Stroma Imaging: Acquisition and Analysis of Clinical Images in Six Different Cancer Entities

“…As a unique feature of [ 99m Tc]Tc-iFAP images, a very low background was achieved as previously reported (Figure 3) [9].…”

“…In Group 1, only of the brain region, and in Group 2, the thoracoabdominal region. The tumor/background ratio is optimal for diagnostic images from 30 min post-injection [9]. However, it was decided 2 h after radiotracer administration to improve the contrast of the images (lesions vs. background).…”

“…Our group previously reported [ 99m Tc]Tc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl)pyrrolidin-2-yl) boronic acid ([ 99m Tc]Tc-iFAP) as a new SPECT radioligand capable of specifically detecting FAP expressed by CAFs located in the cancer stroma and, to our knowledge, the first ligand based on 99m Tc-labeled boron-Pro derivatives [8]. Furthermore, the [ 99m Tc]Tc-iFAP biokinetic-dosimetric evaluation in healthy volunteers and three cancer patients diagnosed with breast, lung, and cervical cancer showed favorable biokinetics and uptake in primary tumor lesions and lymph node metastases, achieving high-quality and high-contrast molecular images [9].…”

Rational Design and Comparison of Novel 99mTc-Labeled FAPI Dimers for Visualization of Multiple Tumor Types

“…Technetium-99m is widely regarded as one of the most commonly used radionuclides in SPECT imaging, which is attributed to its favorable physical properties, including an ideal half-life ( t 1/2 = 6 h; E g = 140 keV), cost-effectiveness, and easy availability. Incompletely compiled data indicate the development of several small-molecule-based FAPIs (Figure ) for 99m Tc labeling in both preclinical and clinical studies. − …”

Synthesis and Preclinical Evaluation of Novel 68Ga-Labeled (R)-Pyrrolidin-2-yl-boronic Acid-Based PET Tracers for Fibroblast Activation Protein-Targeted Cancer Imaging

“…The tumor and kidney uptake values reportedly dropped by ~27% (5.18 ± 0.82 %ID/g) and ~33% (7.46 ± 1.02 %ID/g), respectively, at 2 h pi with minimal uptake in most normal organs. In its clinical study, [ 99m Tc]Tc-iFAP was seen to accumulate in the primary tumors and lymph node metastases of patients with different cancers [ 24 ]. The mean radiation equivalent dose for the kidney (5.2 ± 0.8 mSv) was stated to be more than twice the effective dose (2.3 ± 0.4 mSv) after administrating 740 MBq of the tracer.…”