European Journal of Nuclear Medicine and Molecular Imaging最新文献

Background and Purpose

While [⁶⁸ Ga]Ga-FAPI-04 PET/CT is widely used in various malignant tumors diagnosis, its specificity is challenged by high uptake in benign lesions such as inflammatory lymphadenopathy, bone fractures, and degenerative changes. This study aimed to quantitatively assess and characterize the metabolic heterogeneity of [⁶⁸ Ga]Ga-FAPI-04 uptake in benign and malignant lesions using dynamic total-body PET/CT.

Methods

Dynamic total-body [⁶⁸ Ga]Ga-FAPI-04 PET/CT scans (0–60 min post-injection) were performed on 17 oncology patients. Time-activity curves (TACs) were generated for benign and malignant lesions with high [⁶⁸ Ga]Ga-FAPI-04 uptake. The reversible two-tissue compartment model (2T4k) was used to derive kinetic metrics, including K₁, k₂, k₃, k₄, v_B and V_T. Receiver operating characteristic (ROC) curve analysis was used to determine the cut-off values for differentiating benign and malignant lesions.

Results

The study included 58 malignant and 55 inflammatory lesions with high [⁶⁸ Ga]Ga-FAPI-04 uptake. Malignant lesions exhibited higher K₁ (0.277 ± 0.217 ml/ccm/min vs. 0.221 ± 0.216 ml/ccm/min, P = 0.011), v_B (0.042 ± 0.007 vs. 0.013 ± 0.004, P < 0.001), and lower k₃ (0.267 ± 0.041 1/min vs. 0.481 ± 0.085 1/min, P = 0.008) compared to benign lesions. Lesions were classified into low, medium, and high-probability groups for being malignant based on K₁, k₃ and v_B values, with probabilities of 0%, 50.7%, and 92.0%, respectively (P < 0.001).

Conclusions

Kinetic metrics, particularly K₁, k₃ and v_B values, show promise as imaging biomarkers for distinguishing between benign and malignant lesions with high [⁶⁸ Ga]Ga-FAPI-04 uptake in oncology patients. These metrics reflect the metabolic heterogeneity of the lesions and may improve diagnostic accuracy in oncological imaging.

Background

[⁶⁸Ga]PentixaFor detects C-X-C chemokine receptor type 4 (CXCR4) overexpression in various malignancies, such as multiple myeloma and non-Hodgkin lymphomas, as well as in endocrine and inflammatory disorders. This study aimed to develop an Al¹⁸F-labeled radiotracer derived from LY2510924 for CXCR4-targeted imaging, leveraging the physical and logistical advantages of fluorine-18.

Methods

We designed a CXCR4-specific radioprobe, [¹⁸F]AlF-NOTA-SC, based on LY2510924 by incorporating a triglutamate linker and NOTA chelator to enable Al¹⁸F-labeling. The in vitro CXCR4 affinity was assessed using cell-based binding assays. Subsequently, in vivo pharmacokinetics and tumor uptake of [¹⁸F]AlF-NOTA-SC were assessed in naïve mice and mice with xenografts derived from U87.CD4/U87.CD4.CXCR4 and MM.1 S cells. Finally, biodistribution was determined in a non-human primate using PET-MR.

Results

Compared to Ga-PentixaFor, AlF-NOTA-SC demonstrated similar in vitro affinity for human CXCR4. [¹⁸F]AlF-NOTA-SC was produced with a decay-corrected radiochemical yield of 21.0 ± 7.1% and an apparent molar activity of 16.4 ± 3.6 GBq/µmol. In [¹⁸F]AlF-NOTA-SC binding assays on U87.CD4.CXCR4 cells, the total bound fraction was 7.1 ± 0.5% (58% blocking by AMD3100). In naïve mice, the radiotracer did not accumulate in any organs; however, it showed a significant CXCR4-specific uptake in xenografted tumors (SUVmean_U87.CD4 = 0.04 ± 0.00 (n = 3); SUVmean_{U87.CD4.CXCR4} = 3.04 ± 0.65 (n = 3); SUVmean_MM.1 S = 1.95 ± 0.11 (n = 3)). In a non-human primate, [¹⁸F]AlF-NOTA-SC accumulated in CXCR4 expressing organs, such as the spleen and bone marrow.

Conclusion

[¹⁸F]AlF-NOTA-SC exhibited CXCR4-specific uptake in vitro and in vivo, with fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an ¹⁸F-alternative to [⁶⁸Ga]PentixaFor.

Graphical abstract

Purpose

A noninvasive method for evaluating the infiltration of CD8⁺ T cells in tumors is urgently needed to monitor the response to immunotherapy. This study investigated the performance of a [⁶⁸Ga]Ga-NODAGA-SNA006 in positron emission tomography (PET) imaging of CD8⁺ T cells in patients with solid malignancies.

Methods

This human dose-escalation PET imaging study involved eleven patients (lung cancer, 8; gastric carcinoma, 1; esophageal carcinoma, 2). Approximately 150 MBq of [⁶⁸Ga]Ga-NODAGA-SNA006 with varying nanobody masses (100 µg, 300 µg, 500 µg, 800 µg) was administered, and PET/computed tomography (CT) scans were performed at 15–30, 60–90 and 120 min postinjection (p.i.). Data regarding biodistribution, pharmacokinetics and radiation dosimetry were evaluated. CD8⁺ T-cell infiltration in biopsy samples was also measured via immunohistochemistry (IHC) for correlation analysis with the tumor uptake of [⁶⁸Ga]Ga-NODAGA-SNA006 PET.

Results

[⁶⁸Ga]Ga-NODAGA-SNA006 was well tolerated by all eleven subjects. The highest radioactive uptake was observed in the spleen, followed by the kidneys and bladder. Liver uptake decreased with increasing nanobody mass. Rapid clearance (t_1/2<30 min) of [⁶⁸Ga]Ga-NODAGA-SNA006 from whole blood and serum was observed. Furthermore, ⁶⁸Ga uptake in tumors (SUVmean) exhibited a linear relationship with CD8⁺ T-cell infiltration in biopsy samples (R² = 0.757, p = 0.011), suggesting that the tumor uptake of [⁶⁸Ga]Ga-NODAGA-SNA006 may represent the degree of CD8⁺ T-cell infiltration in the tumor.

Conclusion

The use of [⁶⁸Ga]Ga-NODAGA-SNA006 is safe, feasible, and well tolerated. [⁶⁸Ga]Ga-NONAGA-SNA006 PET imaging can accurately detect CD8 expression inside tumors with favorable pharmacokinetics, thus providing a feasible method for noninvasive quantitative assessment of CD8⁺ T-cell tumor infiltration and monitoring the response to immunotherapy.

Trial Registration

NCT05126927 (19 November 2021, retrospectively registered).

Purpose

Radiolabelled minigastrin (MG) analogues targeting the cholecystokinin-2 receptor (CCK2R) have proven to be a promising approach for peptide receptor radionuclide therapy (PRRT). In this study, we report on the radiopharmaceutical development and standardization of the preparation of [¹⁷⁷Lu]Lu-DOTA-MGS5 using an automated synthesis module. Furthermore, we present the preclinical tests required to move forward towards a first therapeutic clinical trial as well as preliminary clinical dosimetry data.

Methods

Five individual batches of [¹⁷⁷Lu]Lu-DOTA-MGS5 were synthesized and analysed according to predefined quality control specifications. Cell-based experiments and biodistribution studies were performed to evaluate the specific receptor binding and tumour uptake of the radiopharmaceutical formulation. A preclinical dosimetry study was carried out in tumour xenografted mice and a first dosimetry study was performed in a patient with small cell lung cancer.

Results

The automated cassette-based production of [¹⁷⁷Lu]Lu-DOTA-MGS5 resulted in a product with high radiochemical purity of > 98% and high stability. The new radiopharmaceutical showed a favourable biodistribution profile in A431-CCK2R xenografted BALB/c nude mice. Pharmacokinetic data obtained in mice and dosimetry extrapolation demonstrated the feasibility of PRRT. In the preliminary patient-specific dosimetry study, a low risk of toxicity was shown and a mean absorbed dose of 12.5 ± 10.2 (1.2–28) Gy/GBq was calculated for delineable tumour lesions.

Conclusion

The radiopharmaceutical development and the preclinical/clinical results support the initiation of a first clinical trial to evaluate the therapeutic potential of [¹⁷⁷Lu]Lu-DOTA-MGS5 in PRRT.

Purpose

We report the preclinical evaluation of potent long-acting [²²⁵Ac]Ac-EBTATE against SSTR2-positive small cell lung cancer (SCLC) and pancreatic neuroendocrine tumors (pan-NETs).

Methods

The pharmacokinetic, biodistribution, and safety studies were evaluated in healthy female and/or male BALB/c mice after intravenous injections of [²²⁵Ac]Ac-EBTATE. Further biodistribution and radioligand therapy were investigated in female athymic BALB/c nude mice bearing high or low SSTR2-expressing subcutaneous SCLC models NCI-H524 or NCI-H727, respectively, and in a pan-NET model QGP1.SSTR2.

Results

Pharmacokinetics confirmed a prolonged clearance half-life (40.27 ± 9.23 h) while biodistribution in healthy male and female BALB/c mice was similar, with prolonged blood circulation that peaked at 6 h. Biodistribution in subcutaneous xenograft models of NCI-H524 and NCI-H727 showed consistent tumor-uptake with SSTR2-overexpression while the projected human effective doses for males and females were 61.7 and 83.7 millisievert/megabecquerel, respectively. 2 × 34 kBq of [²²⁵Ac]Ac-EBTATE administered 10 days (d) apart, was generally tolerated for 28 days in healthy BALB/c mice as revealed by blood biochemistry, complete blood count, and histopathological examination of H&E-stained organs. Targeted alpha therapy at 2 × 30 kBq of [²²⁵Ac]Ac-EBTATE, injected 10 days apart, resulted in 100% survivals and 80% and 20% complete remissions for NCI-H524 and QGP1.SSTR2 models, respectively. Additionally, [²²⁵Ac]Ac-EBTATE had a dose-dependent response in the NCI-H727 model, with median survivals for 2 × 30 kBq and 2 × 15 kBq groups being 63 d (p < 0.0007), and 47 d (p = 0.0148), respectively.

Conclusions

[²²⁵Ac]Ac-EBTATE is safe and effective against SCLC and pan-NET and therefore warrants clinical investigation.