EJNMMI Research最新文献

Background: Acidic pH values of the tumor microenvironment (TME) have crucial effects on metastatic behavior, host defense, immune regulation and cellular metabolism. Several studies have shown that the acidity of the interstitial space in the TME influences the functions of cancer and stromal cells, particularly regarding immune effects. Changing intratumoral pH might therefore be a potential target for therapy, and pH imaging might guide further developments. We describe radiopharmaceutical probes for positron emission tomography (PET) that exploit the concept of pH-dependent intratumoral hydrolysis of glycosylamine bonds of PET-tracers ([¹⁸F]FDG-4-methoxybenzylamine ([¹⁸F]FDG-4MBA) and [¹⁸F]FDG-benzylamine ([¹⁸F]FDG-BA)) to release [¹⁸F]FDG as functional moiety with the aim to non-invasively image pH changes.

Results: Nuclear magnetic resonance (NMR) spectroscopy demonstrated hydrolysis at pseudo first order and showed pH dependent hydrolysis time, at which 50% of [¹⁹F]FDG-4-methoxybenzylamine ([¹⁹F]FDG-4MBA) was cleaved, ranging from 3 h at pH 7.4 over 60 min at pH 6.9 to 45 min at pH 6.5. Hydrolysis of [¹⁸F]FDG-4MBA in human serum at pH 7,6 was similar to comparable pH without serum (below 10% FDG release after 2 h). The glycosylamines [¹⁸F]FDG-BA and [¹⁸F]FDG-4MBA were relatively stable in vitro at pH 8.3 with less than 15% FDG release from [¹⁸F]FDG-4MBA and less than 10% FDG release from [¹⁸F]FDG-BA within 60 min. Hydrolysis at acidic pH led to [¹⁸F]FDG release at pH 6.0 of 71% from [¹⁸F]FDG-4MBA and 40% from [¹⁸F]FDG-BA at 60 min. In vitro uptake into B16F10 or MC38 cells was pH dependent in contrast to FDG uptake. In a preclinical model bearing the two different acidic subcutaneous tumors (B16F10 and MC38), pH differences in the acidic TME were better discriminated with [¹⁸F]FDG-4MBA than with [¹⁸F]FDG-BA. In vivo neutralization of the acidic extracellular tumor pH prevented pH-dependent cleavage of [¹⁸F]FDG-4MBA resulting in decrease of PET signal.

Conclusion: The determination of pH differences by glycosylamines radiotracers and PET imaging in acidic TME may serve as a novel marker for various questions such as interaction of pH regulation and response to immunotherapies. Notably, even small pH differences in the acidic TME of different tumors, in the same in vivo model, could be discriminated.

Background: Follicular lymphoma (FL), as the most common indolent lymphoma, exhibits reduced survival rates in patients with early progression compared to those without early progression. We aimed to develop a scoring system integrating baseline ¹⁸F-FDG PET/CT tumor metabolic parameters with clinical and other relevant factors to personalize the prediction of disease progression within 24 months (POD24) in FL patients.

Results: Among 123 patients with FL, 33 (26.8%) experienced disease progression within 24 months of follow-up. Among clinical indicators, Lactate dehydrogenase (LDH) [OR: 3.267 (1.055, 10.117), P = 0.040] was an independent risk factor for POD24. Based on the receiver operating characteristic (ROC) curve, the optimal cutoff values for Total lesion glycolysis (TLG), total metabolic tumor volume (TMTV), maximum distance of spread (Dmax), and voxel-based maximum interlesion distance (DmaxVox) in POD24 patients were 628.59 g, 94.08 cm³, 37.22 cm, and 77.92 cm, respectively. Additionally, TLG > 628.59 g [OR: 5.1430 (1.9360, 13.6580), P = 0.001], TMTV > 94.08 cm³ [OR: 11.8530 (2.6730, 52.5640), P = 0.001], Dmax > 37.22 cm [OR: 3.0000 (1.1880, 8.6878), P = 0.028], and DmaxVox > 77.92 cm [OR: 8.0620 (2.2830, 28.4720), P = 0.001] were all risk factors for POD24 patients. The correlation heatmap revealed significant positive correlations between TLG and TMTV (r = 0.95) and between Dmax and DmaxVox (r = 0.99). Patients were stratified into three risk groups based on clinical LDH and imaging parameters TMTV and DmaxVox, with POD24 incidence rates of 5.7%, 26.1%, and 57.1%, respectively (P < 0.001). The constructed integrated model demonstrated the highest predictive performance for POD24 (AUC = 0.759). Decision curve analysis (DCA) and calibration curves confirmed the model's robust predictive capability.

Conclusions: TMTV and DmaxVox on baseline ¹⁸F-FDG PET/CT imaging, along with the clinical parameter LDH, are independent predictors of early disease progression within 24 months (POD24) in patients with FL. A predictive model combining these imaging metrics with clinical parameters effectively stratifies patient risk.

Background: Although molecular tumor-targeting peptides modified with albumin-binding domains can enhance tumor probe uptake and prolong tumor retention time, the prolonged systemic circulation resulting from this modification also increases radiation exposure to normal tissues. This study aims to validate that peptide nucleic acid (PNA)-mediated pretargeted ¹⁶¹Tb radionuclide therapy can slow tumor growth and reduce systemic radiation exposure.

Results: ⁶⁸Ga-EB-RGD, ⁶⁸Ga-cPNA-PNA-EB-RGD, ¹⁶¹Tb-EB-RGD, and ¹⁶¹Tb-cPNA-PNA-EB-RGD all demonstrated labeling efficiencies exceeding 80% and exhibited high stability in phosphate-buffered saline. ¹⁶¹Tb-EB-RGD and ¹⁶¹Tb-cPNA-PNA-EB-RGD showed comparable tumor cell uptake and apoptosis induction (0.95-fold). The binding capability between the pretargeting receptor PNA-EB-RGD and the ligand cPNA reached 80%. The blood biodistribution of the pretargeting group (¹⁶¹Tb-cPNA-PNA-EB-RGD) was 32-fold lower than that of the conventional group (¹⁶¹Tb-EB-RGD) (0.37 ± 0.05%ID/g vs. 11.93 ± 0.62%ID/g, P < 0.05). The biodistribution of ¹⁶¹Tb-EB-RGD and ¹⁶¹Tb-cPNA-PNA-EB-RGD in 4T1 tumor cells was 8.77 ± 0.16%ID/g and 3.86 ± 0.21%ID/g, respectively. The conventional treatment group (¹⁶¹Tb-EB-RGD) showed superior therapeutic efficacy compared to the pretargeting group (¹⁶¹Tb-cPNA-PNA-EB-RGD), which in turn outperformed the control group (345.09 ± 4.93 vs. 100.76 ± 12.20 vs. 183.02 ± 12.94 mm³, P < 0.05). No significant pathological changes were detected in the vital organs of treated animals. Ex vivo tumor analysis supported the treatment trends.

Conclusions: Compared to conventional non-pretargeted radionuclide therapy, PNA-based pretargeted ¹⁶¹Tb radionuclide therapy reduced systemic radiation exposure, significantly decreased hematotoxicity, and suppressed tumor growth in tumor-bearing mice.

Background: Graves' ophthalmopathy (GO) is a challenging autoimmune manifestation of Graves' disease, whose management relies on accurate assessment of inflammatory activity in the extraocular muscles (EOMs). The Clinical Activity Score (CAS), the current gold standard for assessing disease activity, is based on subjective clinical signs. Consequently, objective imaging biomarkers are urgently needed as a complement orbital ^99mTc-DTPA SPECT/CT imaging holds potential, but its quantitative methodology lacks standardization. This study aimed to evaluate the utility of four SPECT/CT-derived quantitative indices for quantifying EOM inflammatory activity in GO.

Results: Group Differences: EOM uptake values for all four indices were significantly higher in the active GO group than in both the inactive and control groups (all P ＜ 0.001). No significant differences were found between the inactive and control groups.

Clinical correlation: All quantitative parameters showed significant positive correlations with the CAS (all p ＜ 0.001).

Diagnostic performance: ROC curve analysis confirmed that all indices effectively differentiated active from inactive GO, with SUV_mean yielding the superior diagnostic efficacy (AUC = 0.887).

Conclusions: In summary, this study confirms that quantitative indices from orbital ^99mTc-DTPA SPECT/CT, particularly SUV_mean-3D, effectively quantify EOMs inflammatory activity in GO. Parameters derived using CT-based 3D VOI delineation (SUV_mean-3D and SUV_max-3D) demonstrated superior reliability over traditional methods. Among all indices, SUV_mean-3D demonstrated superior diagnostic efficacy (AUC = 0.887) for differentiating active from inactive disease. These indices provide an objective tool for quantifying GO severity and monitoring disease changes during patient follow-up. This capability is vital for monitoring treatment response, guiding therapeutic decisions, and serving as a potential endpoint in clinical trials.