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.

Neuroendocrine tumors (NETs) are slow-growing tumors that express high levels of somatostatin receptors (SSTRs). Recent studies have shown the superiority of radiolabeled SSTR antagonists in theranostics compared to agonists. In this prospective study, we compared the diagnostic efficacy between [⁶⁸Ga]Ga-DOTANOC and [⁶⁸Ga]Ga-DATA^5m-LM4 in the detection of primary and metastatic lesions in patients with well differentiated gastroenteropancreatic (GEP) NETs. Histologically proven GEP-NET patients underwent [⁶⁸Ga]Ga-DOTANOC & [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT scans, which were analyzed. The qualitative analysis involved the visual judgment of radiotracer uptake validated by the morphological findings using CT, which was considered as the reference standard. Quantitative comparisons were presented as the standardized uptake value (SUV) corrected for lean body mass: SULpeak, SULavg, and tumor-to-background ratios (TBR). In total, 490 lesions were confirmed via diagnostic CT. The lesion-based sensitivity of [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT was 94.28% (462/490) and 83.46% (409/490) for [⁶⁸Ga]Ga-DOTANOC PET/CT (p < 0.0001). [⁶⁸Ga]Ga-DATA^5m-LM4 had statistical significance over [⁶⁸Ga]Ga-DOTANOC in liver metastases [100% vs. 89.4%; p < 0.0001 (292 vs. 253 {283 lesions on CT})] and bone metastases [100% vs. 82.9%; p = 0.005 (45 vs. 34 {41 lesions on CT})]. Statistical significance was also noted for the TBR SULpeak of the primary and liver lesions. [⁶⁸Ga]Ga-DATA^5m-LM4 showed better sensitivity and a higher target-to-background ratio than [⁶⁸Ga]Ga-DOTANOC PET/CT. [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT can be used to quantify the extent of skeletal and liver metastases for better planning of SSTR agonist- or antagonist-based therapy.

Aiming to expand the application of the SST₂R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH₂) beyond [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT (DATA^5m, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA⁵-LM4 (AAZTA⁵, 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [¹¹¹In]In-AAZTA⁵-LM4 and [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 were compared in HEK293-SST₂R cells and double HEK293-SST₂R/wtHEK293 tumor-bearing mice using [¹¹¹In]In-DOTA-LM3 and [¹⁷⁷Lu]Lu-DOTA-LM3 as references. The biodistribution of [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 was additionally studied for the first time in a NET patient. Both [¹¹¹In]In-AAZTA⁵-LM4 and [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 displayed high and selective targeting of the HEK293-SST₂R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 in the patient according to SPECT/CT results in a monitoring time span of 4–72 h pi. In view of the above, we may conclude that [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST₂R-expressing human NETs, based on previous [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [¹¹¹In]In-AAZTA⁵-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available.

Purpose: This study aimed to assess the biodistribution and radiation dosimetry of ⁶⁸Ga-DATA^5m LM4 in patients with gastroenteropancreatic neuroendocrine tumors. Patients and Methods: Eight patients (5 females and 3 males) with various gastroenteropancreatic neuroendocrine tumors were included in the study. Each patient underwent 3 whole-body PET scans at 10, 60, and 120 minutes after receiving an IV injection of approximately 162.5 MBq of ⁶⁸Ga-DATA^5m LM4. Organs considered for dosimetric analysis included the liver, heart, spleen, kidneys, adrenal glands, and lumbar vertebrae (L2 to L4). Dosimetric calculations were performed using the OLINDA/EXM 2.2 software. Results: Physiological uptake of ⁶⁸Ga-DATA^5m LM4 was observed in the pituitary gland, spleen, liver, adrenal glands, and the urinary tract (kidneys and urinary bladder) for all patients. The kidneys received the highest absorbed doses at (4.77E-02 ± 1.49E-02 mSv/MBq). The mean effective dose was 2.61E-03 ± 5.99E-04 mSv/MBq. Conclusions: ⁶⁸Ga-DATA^5m LM4 injection is safe and is primarily excreted through urine, delivering the highest radiation dose to the kidneys.