Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC‑1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides 177Lu and 225Ac. This was improved with the dimer DOTAGA.(SA.FAPi)2, but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi)2 and DOTAGA.Glu.(FAPi)2. were synthesized and quantitatively radiolabeled with 68Ga, 90Y, 177Lu and 225Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [225Ac]Ac-DOTAGA.Glu.(FAPi)2 in PBS. In vitro affinity studies resulted in subnanomolar IC50 values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [natLu]Lu-DOTAGA.Glu.(FAPi)2. In a first proof-of-principle patient study (medullary thyroid cancer), [177Lu]Lu-DOTAGA.Glu.(FAPi)2 was compared to [177Lu]Lu-DOTAGA.(SA.FAPi)2. High uptake and long tumor retention was observed in both cases, but [177Lu]Lu-DOTAGA.Glu.(FAPi)2 significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi)2 showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTAGA.Glu.(FAPi)2 and [225Ac]Ac-DOTAGA.Glu.(FAPi)2 appear promising for translational application in patients.
This study aimed to compare the diagnostic performance of [68Ga]Ga-DOTA.SA.FAPi with that of [18F]F-FDG PET/CT in detecting primary and metastatic lesions of breast cancer. [18F]F-FDG and [68Ga]Ga-DOTA.SA.FAPi PET/CT scans of histologically proven breast cancer patients were compared according to patient-based and lesion-based analysis. Forty-seven patients with a mean age of 44.8 ± 9.9 years (range: 31–66 years) were evaluated. A total of 85% of patients had invasive ductal carcinoma, and 15% had invasive lobular carcinoma. The tracer uptake [SULpeak, SULavg, and the median tumor-to-background ratio (TBR)] was significantly higher in [68Ga]Ga-DOTA.SA.FAPi than with [18F]F-FDG PET/CT for lymph nodes, pleural metastases, and liver lesions (p < 0.05). However, for brain metastasis, only the median TBR was significantly higher (p < 0.05) compared to [18F]F-FDG. In patient-based analysis the sensitivity of [68Ga]Ga-DOTA.SA.FAPi PET/CT was higher, but not significant than that of [18F]F-FDG PET/CT in the detection of both primary tumors and metastatic lesions. According to lesion-based analysis, on diagnostic CT, 47 patients had 44 primary tumors, 248 lymph nodes, 15 pleural, 88 liver, and 42 brain metastases. [68Ga]Ga-DOTA.SA.FAPi scan identified more abnormal lesions than [18F]F-FDG in all the primary and metastatic sites with a maximum marked difference in the primary site [88.6% vs. 81.8%; p-0.001], lymph nodes [89.1% vs. 83.8%; p-0.0001], pleural metastases [93.3% vs. 73%; p-0.096] and brain metastasis [100% vs. 59.5%; p-0.0001]. [68Ga]Ga-DOTA.SA.FAPi PET/CT was superior to [18F]F-FDG PET/CT in the imaging of breast cancers.
Purpose
[18F]F-FDG is a standard and valuable diagnostic imaging modality for radioiodine-resistant follicular-cell derived thyroid cancers (RAI-R FCTC). Recently, molecular imaging probes targeting cancer-associated fibroblasts (CAFs) have gained prominence and have proved to be a potential alternative to [18F]F-FDG PET/CT in oncological imaging. This study aimed to compare the diagnostic efficacy of [68Ga]Ga-DOTA.SA.FAPi and [18F]-FDG PET/CT in RAI-R FCTC patients.
Methods
The retrospective study included 117 RAI-R FCTC patients [68 females, 49 males; mean age: 53.2 ± 11.7 years]. Qualitative assessment parameters included comparing patient-based and lesion-based visual interpretation of both scans. The quantitative assessment included comparing standardized uptake values corrected for lean body mass (SULpeak and SULavg). The findings on both scans were validated with the morphological findings of the diagnostic computed tomography.
Results
60 had single remnants, and 9 had bilateral remnant lesions with a complete concordance in the detection rate on both PET scans. [68Ga]Ga-DOTA.SA.FAPi showed a higher detection efficiency rate for lymph nodes (sensitivity 95.4% vs 86.6%, p < 0.0001), liver metastases (100% vs. 81.3%; p < 0.0001), brain metastasis (100% vs. 43.4%; p-0.0003). Except for brain metastasis (SULpeak [68Ga]Ga-DOTA.SA.FAPi vs. [18F]-FDG: 13.9 vs. 6.7) and muscle metastasis (SULpeak FAPI vs. FDG: 9.56 vs. 5.62), there was no significant difference in the median SUL uptake values between the radiotracers.
Conclusion
[68Ga]Ga-DOTA.SA.FAPi showed a superior detection efficiency for lymph nodes, liver, bowel, and brain metastasis. Unlike [18F]F-FDG, [68Ga]Ga-DOTA.SA.FAPi can be used as theranostic probes in RAI-R FCTC. [68Ga]Ga-DOTA.SA.FAPi provided a complimentary benefit to the [18F]F-FDG-PET/CT scan in the imaging of RAI-R FCTC.
This review describes the basic principles of radiometal-theranostics and its dawn based on the development of the positron-emitting 86Y and 86Y-labeled radiopharmaceuticals to quantify biodistribution and dosimetry of 90Y-labeled analogue therapeutics. The nuclear and inorganic development of 86Y (including nuclear and cross section data, irradiation, radiochemical separation and recovery) led to preclinical and clinical evaluation of 86Y-labeled citrate and EDTMP complexes and yielded organ radiation doses in terms of mGy/MBq 90Y. The approach was extended to [86/90Y]Y-DOTA-TOC, yielding again yielded organ radiation doses in terms of mGy/MBq 90Y. The review further discusses the consequences of this early development in terms of further radiometals that were used (68Ga, 177Lu etc.), more chelators that were developed, new biological targets that were addressed (SSTR, PSMA, FAP, etc.) and subsequent generations of radiometal-theranostics that resulted out of that.
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