Biodistribution, pharmacokinetics, dosimetry of [68Ga]Ga-DOTA.SA.FAPi, and the head-to-head comparison with [18F]F-FDG PET/CT in patients with various cancers.

PURPOSE: [68Ga]Ga-labeled fibroblast activation protein inhibitors ([68Ga]Ga-FAPi) have shown promising preclinical and clinical results in PET imaging. The present study aimed to evaluate the biodistribution, pharmacokinetics, and dosimetry of [68Ga]Ga-DOTA.SA.FAPi, another modified FAPi tracer, and performed a head-to-head comparison with [18F]F-FDG PET/CT scans in patients with various cancers. METHODS: In this prospective study, patients underwent both [18F]F-FDG and [68Ga]Ga-DOTA.SA.FAPi PET/CT scans 60 min post-injection (p.i.). Dosimetry studies were conducted in three patients using [68Ga]Ga-DOTA.SA.FAPi serial time-point imaging. The absorbed dose was calculated using OLINDA/EXM 2.2 software. Quantification of the uptake of the tracers was assessed using standardized uptake values corrected for lean body mass (SUL). RESULTS: Fifty-four patients (mean age; 48.4 years) with 14 types of cancers involving 37% breast, 24% lung, 7.4% head and neck (H&N), and remaining 31.6% patients with other histologies were evaluated prospectively. Physiological uptake of [68Ga]Ga-DOTA.SA.FAPi was observed in the liver, kidneys, pancreas, heart contents, and to a lesser extent in the lacrimals, oral mucosa, salivary glands, and thyroid glands. Uptake in the target lesions on [68Ga]Ga-DOTA.SA.FAPi scan was initiated at 10 min, and no additional lesions were detected in the delayed acquisition time points. The pancreas was the organ with the highest absorbed dose (5.46E-02 mSv/MBq). While the patient-based comparison between the radiotracers revealed complete concordance in the detection of primary, pleural thickening, bone and liver metastases, and second primary malignancy, discordant findings were observed in the detection of lymph node (7.5%), lung nodules (5.6%), and brain metastases (2%). According to the site of primary disease, patients with H&N cancers demonstrated the highest SULpeak and average (avg) values on [68Ga]Ga-DOTA.SA-FAPi which was similar to the values of [18F]F-FDG [(SULpeak: 15.4 vs. 14.2; P-0.680) (SULavg: 8.3 vs. 7.9; P-0.783)]. The lowest uptake was observed in lung cancers with both the radiotracers [(SULpeak: 5.8 vs. 7.4; P-0.238) (SULavg: 4.9 vs. 5.3; P-0.313)]. A significantly higher SULpeak and SULavg for brain metastases to normal brain parenchyma ratios were observed on [68Ga]Ga-DOTA.SA.FAPi in contrast to the [18F]F-FDG values {SULpeak: median: 59.3 (IQR: 33.5-130.8) versus 1.5 (1-2.3); P-0.028}. Except for brain metastases, comparable SULpeak and average values were noted between the radiotracers in all other regions of metastases with no significant difference. CONCLUSION: [68Ga]Ga-DOTA.SA.FAPi is a promising alternative among the FAPI class of molecules and performed well as compared to standard-of-care radiotracer [18F]F-FDG in the diagnosis of various cancers.

First-In-Human Results on the Biodistribution, Pharmacokinetics, and Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2.

Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers. The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were administered in two different groups of patients. Three patients (mean age-50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2-3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age-51 years) were treated with 1.48 GBq (IQR: 0.6-1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (p < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5-70.1) vs. 23.1 h (IQR: 17.8-31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3-94.6) vs. 14 h (IQR: 12.8-15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230-1.810) Gy/GBq and 6.70 (IQR: 3.40-49) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.