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.

Background: A theranostic probe for accurate staging and treatment is crucial for the management of medullary thyroid cancers (MTCs). The abundance of stroma in most of thyroid cancers, including MTC, opens new avenues for selecting cancer-associated fibroblasts (CAFs) as new molecular imaging and therapeutic targets. [ ⁶⁸ Ga]Ga-labeled fibroblast activation protein inhibitor (FAPi) molecules have gained importance as alternative molecular imaging agents in the imaging of thyroid cancers. The purpose of this study was to compare the detection efficiency of primary and metastatic lesions of MTCs between [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi and [ ⁶⁸ Ga]Ga-DOTANOC positron emission tomography (PET) radiotracers. Materials and Methods: In this retrospective study, [ ⁶⁸ Ga]Ga-DOTANOC and [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi PET/CT (computed tomography) images were compared using patient-based and lesion-based analysis in patients with MTC for follow-up assessment. The quantitative assessment included comparing standardized uptake values corrected for lean body mass (SULpeak) and tumor-to-background ratios (TBR). The findings on both scans were validated with the morphological findings of the diagnostic CT. Results: Twenty-seven patients (21 males and 6 females) with a mean age of 42.4 ± 13.2 years (range 14–66 years) were included in the study. [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi had similar sensitivities as that of [ ⁶⁸ Ga]Ga-DOTANOC PET/CT for detecting primary tumors (100% [18 of 18] vs. 94.4% [17 of 18], p = 0.979) involved lymph nodes (98.3% [118 of 120] vs. 95% [114 of 120], p = 0.288), and brain metastases (100%). [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi demonstrated significantly higher sensitivities than [ ⁶⁸ Ga]Ga-DOTANOC PET/CT for detecting lung nodules (93.5% [87 of 93] vs. 68.9% [64 of 93], p < 0.0001), liver (100% [105 of 105] vs. 46.4% [49 of 105], p < 0.0001), bone (92.4% [110 of 119] vs. 76.5% [91 of 119], p = 0.001), and pleural metastases 98.2% versus 0%. Higher uptake values and TBR values were reported with [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi compared with that of [ ⁶⁸ Ga]Ga-DOTANOC. Conclusion: [ ⁶⁸ Ga]Ga-DOTA.SA.FAPi outperformed [ ⁶⁸ Ga]Ga-DOTANOC PET/CT in the detection of distant metastases with both patient-based and lesion-based analysis in MTCs.

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.

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.

Purpose: This study aimed to compare the diagnostic efficacy of [⁶⁸Ga]Ga-DOTA.SA.FAPi and [¹⁸F]F-FDG PET/CT for detecting primary and metastatic lesions in sarcoma patients. Materials and Methods: The analysis included both patient-based and lesion-based comparisons of PET/CT scans in individuals with histologically confirmed sarcoma. Results: A total of 23 sarcoma patients (mean age 43.0 ± 16.5 years; range: 21–76 years) underwent both [¹⁸F]F-FDG and [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT scans. Histological distribution included 30% synovial sarcoma, 13% liposarcoma, and 21.7% leiomyosarcoma, with 70% of patients presenting with distant metastases. Detection rates for primary tumors were similar between [⁶⁸Ga]Ga-DOTA.SA.FAPi and [¹⁸F]F-FDG PET/CT (85.7% vs 100%, P = 0.149). Lymph node detection rates were also comparable (80% vs 100%, P = 0.146). Lesion-based analysis revealed that [⁶⁸Ga]Ga-DOTA.SA.FAPi detected 220 lesions (83% efficiency) compared with 249 lesions (94% efficiency) for [¹⁸F]F-FDG (P < 0.0001). Notably, [⁶⁸Ga]Ga-DOTA.SA.FAPi demonstrated superior detection of liver (54 vs 38 lesions, P < 0.0001) and bone metastases (125 vs 102 lesions, P < 0.0001). Conclusions: Our study shows that although [¹⁸F]F-FDG PET/CT offers superior overall lesion detection efficiency, [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT excels in identifying specific metastatic sites, particularly in bone and liver. These findings highlight the complementary roles of both imaging modalities in sarcoma evaluation.