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

Tumor microenvironment fibroblasts overexpress the fibroblast activation protein (FAP). We recently reported the preclinical evaluation of [Tc-99m]Tc-iFAP as a new SPECT radioligand capable of detecting FAP. This research aimed to evaluate the kinetic and dosimetric profile of [Tc-99m]-iFAP in healthy volunteers, and to assess the radioligand uptake by different solid tumors in three cancer patients. [Tc-99m]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 [Tc-99m]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, infinity) 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 [F-18]FDG PET/CT scan underwent whole-body, chest, and abdominal SPECT/CT scanning after [Tc-99m]Tc-iFAP (740 MBq) administration. Both imaging methods were compared visually and quantitatively. Oncological diagnoses were performed histopathologically. The results showed favorable [Tc-99m]Tc-iFAP biodistribution and kinetics due to rapid blood activity removal (t(1/2)alpha = 2.22 min and t(1/2)beta = 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. [Tc-99m]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 [F-18]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 [Tc-99m]Tc-iFAP in the diagnosis and prognosis of different types of solid tumors.