Molecular Imaging and Biology最新文献

Molecular imaging exhibits remarkable potential in immune cell tracking and advancing personalized clinical management, providing not only diagnostic and prognostic information but also enabling treatment efficacy quantification and therapeutic optimization. Macrophages play an essential role in the pathogenesis and progression of various cardiovascular diseases. This review comprehensively examines the characteristics of diverse molecular imaging modalities and their applications in macrophage imaging, encompassing major cardiovascular conditions, including atherosclerosis, myocardial infarction, and cardiac transplantation. We anticipate that advancements in novel noninvasive molecular imaging technologies for macrophages will ultimately facilitate clinical diagnosis, outcome prediction, treatment strategy formulation, and therapy response monitoring, thereby providing critical technical support for precision medicine practice.

Rationale: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β "trap") and human immunoglobulin 1 antibody which blocks programmed cell death ligand 1 (PD-L1). This trial aimed to investigate the biodistribution of ⁸⁹Zr-bintrafusp alfa in patients with NSCLC with PD-L1 expressing tumors.

Methods: Five lung cancer patients were recruited with PD-L1 staining more than 1% of tumor cells. Patients underwent ⁸⁹Zr-bintrafusp alfa intravenous infusion (100 mg IV) on Day 1 followed by sequential PET imaging to determine the biodistribution of ⁸⁹Zr-bintrafusp alfa. Patients then received treatment with bintrafusp alfa (1200 mg IV) on day 15 and 29, with the latter including further ⁸⁹Zr-bintrafusp alfa to determine the effects of bintrafusp alfa treatment on receptor occupancy. Patients continued with bintrafusp alfa monotherapy, or in combination with chemotherapy for those without objective response to monotherapy, until disease progression or unacceptable toxicity. The study stopped after five patients due to the overall cessation of the bintrafusp alfa program.

Results: ⁸⁹Zr-bintrafusp alfa imaging was feasible and well tolerated. All patients showed tumor specific uptake without normal tissue uptake. There was no correlation between uptake and tissue PD-L1 expression or outcomes, likely due to sample size. Inter- and intra-patient heterogeneity was observed and optimal treatment regimens will need to address this in future.

Conclusions: ⁸⁹Zr-bintrafusp alfa imaging is safe, feasible and provides relevant tumor targeting information for patient selection and treatment.

Purpose: Lymphocyte-activation gene 3 (LAG-3), a next-generation immune checkpoint, has emerged as a promising therapeutic target, but noninvasive tools for evaluating LAG-3 expression remain limited. Herein, we explored an antibody-dependent molecular imaging strategy for noninvasive detection based on a LAG-3-specific antibody, HuL13.

Procedures: The anti-LAG-3 antibody HuL13 was radiolabeled with ¹²⁴I via electrophilic substitution. LAG-3-expressing A549 cells were constructed by infection with the lentivirus. The specificity and affinity of ¹²⁴I-HuL13 to LAG-3 receptor were evaluated by cell uptake assay and saturation binding assay. Micro-PET/CT imaging studies were conducted in BALB/c nude mice bearing LAG-3⁺ A549 tumors. Immunohistochemistry (IHC) validated LAG-3 expression in tumors.

Results: The ¹²⁴I-HuL13 exhibited a good radiochemical yield of 95.59 ± 1.27%, high radiochemical purity (RCP, > 99%), and excellent stability. Cell binding assays demonstrated that ¹²⁴I-HuL13 had a higher binding ability to LAG-3⁺ A549 cells compared to control cells. The equilibrium dissociation constant (Kd) of ¹²⁴I-HuL13 was 23.02 nM for LAG-3⁺ A549 cells. In vivo pharmacokinetics revealed favorable metabolic stability (t_1/2β = 12.07 h). Micro-PET/CT images showed that ¹²⁴I-HuL13 significantly accumulated in LAG-3⁺ A549 tumor from 24 h after injection (SUVmax = 0.34 ± 0.03 at 24 h), and high contrast tumor to background imaging was clearly observed. IHC confirmed LAG-3 expression correlated with probe uptake.

Conclusions: ¹²⁴I-HuL13 is a novel LAG-3-targeted PET imaging radiotracer with excellent stability. This study highlights ¹²⁴I-HuL13 as a robust tool for noninvasive LAG-3 imaging, offering potential for optimizing LAG-3-targeted immunotherapy in clinical settings.

Introduction: The adenosine monophosphate-activated protein kinase (AMPK) induces glucose uptake by increasing the expression of glucose transporter 4 (GLUT4), and [¹⁸F]Fluorodeoxyglucose (FDG) is readily transported into tissues with high GLUT4 expression. Thus, positron emission tomography with FDG (FDG-PET) could serve as an important pharmacodynamic readout of AMPK activation. In this study, the impact of treatment with the pan-AMPK activator MK-8722 on FDG uptake was evaluated in rats and Rhesus monkeys.

Methods: Rats were evaluated with FDG-PET following intravenous (IV) or oral (PO) administration of MK-8722. Rhesus monkeys were orally dosed and evaluated with FDG-PET. FDG uptake was measured in skeletal and cardiac muscle, and the incorporation rate was calculated using the Patlak graphical method.

Results: In rats, the highest IV dose of MK-8722 (5 mg/kg) and both PO doses (4 mg/kg and 10 mg/kg) given 4 h prior to FDG-PET resulted in a significant increase in forelimb skeletal muscle FDG uptake (p < 0.01). In Rhesus monkeys, chronic oral administration of 10 mg/kg MK-8722 QD resulted in significantly higher FDG uptake in bicep skeletal muscle than vehicle treatment after 2 and 4 weeks of treatment (p < 0.01), but no difference was observed after 5 weeks of drug washout (p > 0.05). FDG uptake in cardiac muscle was significantly reduced with MK-8722 treatment in rats, but no significant changes in cardiac muscle FDG uptake were measured in Rhesus monkey.

Conclusions: FDG-PET can be used as a pharmacodynamic readout for systemic pharmacological activation of AMPK for preclinical studies and potentially be extended to study humans.

Background: Increased amino acid transport in gliomas allows imaging of metabolically active tumor volume by PET. Tryptophan analog PET radiotracers can provide additional information by tracking tumoral metabolism via the upregulated immunosuppressive tryptophan-kynurenine pathway. We tested the recently developed tryptophan analog PET tracer [¹⁸F]-fluoro-ethyl-L-tryptophan ([¹⁸F]FETrp) for detecting post-treatment glioblastoma while using a non-invasive approach to generate parametric tryptophan metabolic maps and comparing them with static tracer uptake maps and contrast-enhanced MRI.

Methods: Five patients (age: 22-67 years) with previously treated glioblastoma underwent [¹⁸F]FETrp PET/CT imaging. A dynamic acquisition protocol sampled the brain and blood pool non-invasively using the FlowMotion Multiparametric PET software (Siemens Healthineers). Parametric brain images of the unidirectional uptake rate constant (K_i), characterizing irreversible tryptophan trapping and the volume of distribution (V_D) were fused with static uptake (SUV) maps and contrast-enhanced brain MRI. Voxels with elevated K_i, V_D, and SUV were defined, and their spatial associations with contrast-enhanced volumes were characterized by their % volume overlap and the distance between their centroids.

Results: A substantial spatial volume overlap was observed between MRI contrast-enhancing regions and elevated static [¹⁸F]FETrp uptake and V_D. In contrast, the overlap between contrast-enhancing regions and elevated K_i metabolic volumes was low (0-16%), with high K_i areas extending deeper into non-enhancing brain (7-33 mm centroid distance). These non-enhancing high K_i areas showed new contrast-enhancement on follow-up MRI, consistent with tumor progression.

Conclusions: Areas of high tryptophan metabolism detected by [¹⁸F]FETrp PET-derived parametric (K_i) maps extend outside the contrast-enhancing glioblastoma mass in adjacent non-enhancing brain regions that can be missed or underestimated by static uptake images. Consequently, [¹⁸F]FETrp PET metabolic maps have the potential for enhanced detection of non-enhancing glioma infiltration for improved radiation or surgical treatment planning.

Background: Pafolacianine (Cytalux^®) represents the first FDA-approved tumor-specific fluorescence imaging agent, demonstrating efficacy in ovarian cancer through folate receptor-α (FR-α) targeting. Given the need for improved intraoperative margin assessment in head and neck squamous cell carcinoma (HNSCC), where positive surgical margins occur in 10-30% of cases, we investigated the potential utility of pafolacianine for fluorescence-guided surgery in HNSCC models.

Objective: To evaluate the feasibility of visualizing HNSCC using pafolacianine in vitro, in vivo, and clinical tissue analysis, with comparison to fluorescence-guided surgery agents that have been successful in patients.

Methods: HNSCC cell lines (FaDu, UMSCC47) were treated with escalating concentrations of pafolacianine (0-500 nM) and assessed for binding at 1 and 24 h. Nude mice bearing HNSCC xenografts (FaDu, UMSCC47) received intraperitoneal injection of pafolacianine (10 nmol) with fluorescence imaging at multiple timepoints. Immunohistochemistry analysis of patient samples (n = 8 tumor, n = 8 normal) evaluated FR-α and FR-β expression. Panitumumab-IRDye800CW served as a positive control for comparison.

Results: In vitro analysis demonstrated minimal pafolacianine binding across all HNSCC cell lines, with fluorescence intensities similar to or lower than the FR-α-negative A549 control cell line. In vivo imaging revealed poor tumor localization with mean fluorescence intensity (MFI) of 7.39 (FaDu) and 6.97 (UMSCC47), substantially lower than non-target tissues including skin. Immunohistochemistry analysis showed no statistically significant difference in FR-α expression between tumor and normal tissue (p > 0.05). For comparison, panitumumab-IRDye800CW demonstrated robust tumor targeting with MFI of 32.14 (FaDu) and 14.98 (UMSCC47).

Conclusions: This study demonstrates that pafolacianine exhibits limited utility for fluorescence-guided surgery in HNSCC due to insufficient FR-α expression and poor tumor-to-background contrast. These negative findings provide crucial evidence against the clinical translation of pafolacianine for HNSCC applications and highlight the importance of target expression validation in precision medicine approaches.

Clinical relevance: Negative studies such as this are essential for evidence-based clinical decision-making, preventing unnecessary resource allocation and potential patient exposure to ineffective interventions. These findings inform the broader fluorescence-guided surgery field and support continued investigation of alternative targeting strategies for HNSCC.

Purpose: Wound healing process in lung injury involves the activation of the mitogen-activated protein kinase (MAPK) pathway. In this study, we investigated the role of the MAPK pathway in wound healing in a murine model of emphysema using hyperpolarized ¹²⁹Xe (HP ¹²⁹Xe) magnetic resonance imaging (MRI).

Procedures: Porcine pancreatic elastase was administered intratracheally to 25 mice to induce lung injury. Temporal changes in pulmonary gas exchange function were monitored using HP ¹²⁹Xe MRI, revealing a significant decline in function one day after elastase administration. Treatments with ethyl pyruvate (EP) and nicorandil (Nic), which upregulate and downregulate the MAPK pathway, respectively, were initiated in 12 and 7 of the 25 mice, respectively, and continued for 20 days. Over the 21-day period, HP ¹²⁹Xe MRI was performed to monitor the disease progression and treatment efficacy through changes in the metrics of gas exchange and fractional ventilation.

Results: HP ¹²⁹Xe MRI showed that EP significantly improved gas exchange function 14 days after elastase administration, whereas Nic did not show any improvement. Ventilatory function also improved in the EP group, but not in the Nic group, 14 days after elastase administration. Histological analysis showed that EP repaired tissue damage to a level similar to that observed in healthy mice, whereas Nic did not.

Conclusions: In the present study, we provide some insight into the role of the MAPK pathway in wound healing in elastase-induced lung injury, as assessed using the HP ¹²⁹Xe MRI protocol.

Background: CD38 is an excellent biomarker and therapeutic target for multiple myeloma due to its high expression on cancerous cells in comparison to healthy cells.

Purpose: We aimed to adapt Isatuximab as a PET imaging agent to detect CD38 positive multiple myeloma.

Methods: In vitro studies confirmed the specificity of [⁸⁹Zr]Zr-DFO-Isatuximab in CD38 + OPM-2 and MM.1S cells. Upregulation of CD38 was performed using pomalidomide and ricolinostat. Athymic nude mice were implanted with OPM-2 tumors and PET/CT images were collected 24 h, 3d, and 7d post-injection. Dosimetry data was collected from male and female mice and calculated using OLINDA. Three productions of [⁸⁹Zr]Zr-DFO-Isatuximab were produced using GMP techniques and validated for use in the clinic.

Results: Upregulation of CD38 was observed in vitro in CD38 + cells when treated with either pomalidomide or ricolinostat. In vivo evaluation of [⁸⁹Zr]Zr-DFO-Isatuximab showed high selectivity in OPM-2 xenografts. Blocking with an excess of unlabeled Isatuximab reduced the tumor accumulation of [⁸⁹Zr]Zr-DFO-Isatuximab by 45.5-48.5% confirming the in vivo specificity of this radiotracer. Dosimetry calculations were performed and showed an estimated effective dose of 0.359 mSv/MBq in females and 0.327 mSv/MBq in males. Three clinical grade [⁸⁹Zr]Zr-DFO-Isatuximab doses using good manufacturing practices were synthesized which passed all quality control requirements and were stable up to 6 h, thus validating this compound for use in future clinical trials.

Conclusion: [⁸⁹Zr]Zr-DFO-Isatuximab showed high specificity to CD38 positive cells, had estimated effective doses comparable to other clinically relevant ⁸⁹Zr-labeled antibodies, and can be prepared using GMP practices for clinical use.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) represents a highly aggressive malignancy with a 5-year survival rate below 10% and poor prognosis. Early diagnosis of PDAC remains a significant challenge due to its nonspecific symptomatology, insufficient reliable biomarkers, aggressive tumor progression with early metastatic spread, and limited effective screening protocols. Recent research indicates cannabinoid type 2 receptor (CB2R) overexpression in PDAC, leading to the development of [¹⁸F]JR-1004 as a potential CB2R-targeted PET probe to address diagnostic challenges in this aggressive malignancy.

Procedures: The probe development utilized computer-aided drug design, incorporating modifications to a triaryl sulfonamide CB2R inverse agonist lead compound. Essential pharmacophoric elements (central sulfonamide, flanking aromatic rings) were preserved, while the para-methoxy group underwent conversion to a tosylate precursor for radiolabeling. Radiolabeling with ¹⁸F was performed using a JiRui OnePlatform 3.1 s synthesizer (synthesis time: 70 min).

Results: The radiochemical purity and yield achieved values exceeding 95% and 16.7%, respectively. In vitro studies confirmed [¹⁸F]JR-1004's specific binding affinity in CB2R-overexpressing cells, with uptake significantly reduced by a CB2R antagonist administration. PET imaging in PDAC mouse models revealed significant accumulation in tumor regions, with receptor specificity validated through CB2R blocking studies. Biodistribution analysis revealed primary probe metabolism through the hepatobiliary system, with maximal uptake in the liver and pancreas. The probe's targeting profile demonstrates notable improvements for PDAC detection compared to the relatively nonspecific uptake patterns of [¹⁸F]FDG PET in pancreatic imaging.

Conclusions: This investigation presents an innovative molecular imaging approach for early PDAC diagnosis, exhibiting considerable potential for clinical implementation.