PET Tracer Research Articles

αvβ6-integrin targeted PET/CT imaging in pancreatic cancer patients using 68Ga-Trivehexin

Purpose68Ga-Trivehexin is a PET tracer targeting αvβ6-integrin, a transmembrane receptor that is frequently expressed by pancreatic cancer cells. This study aimed to determine the biokinetics, image contrast, and acquisition parameters for 68Ga-Trivehexin PET imaging in pancreatic cancers.Methods44 patients with pancreatic cancer underwent Trivehexin PET/CT between June 2021 and November 2022 (EK-242052023). Biokinetics and -distribution were extracted. Previous imaging follow-up imaging, and histological findings were used as reference standards. A one-way ANOVA test, followed by Tukey HSD post-hoc test was conducted. T-tests for subgroups ± chemotherapy prior to PET were performed. Based on dynamic PET data (n = 11) recorded over 45 min, time-activity curves were generated.Results68Ga-Trivehexin PET/CT detected 40 pancreatic cancers, SUVmax 12.6; range [5.1–30.8]; 39 liver metastases, SUVmax 7.9 [2.7–16.3]; 21 lymph node metastases, SUVmax 8.6 [2.5–15.0]; 17 peritoneal metastases, SUVmax 9.5 [4.0–16.9] and 14 other metastases, SUVmax 7.2 [2.9–13.1]. Tukey post-hoc analysis revealed significant differences for SUVmax in pancreatic cancer compared to SUVmax in liver metastases [4.74, 95%-CI (1.74, 7.75)], for SUVmax in pancreatic cancer to SUVmax in lymph node metastasis [4.07, 95%-CI (0.47, 7. 67)], for tumor-to-liver ratio (TLR) of liver metastasis to TLR of pancreatic cancer [1.82, 95%-CI (0.83, 2.80)], for TLR of pancreatic cancer to TLR of peritoneal carcinomatoses [−1.88, 95%-CI (−3.15, −0.61)], and TLR of pancreatic cancer to TLR of pleural carcinomatosis [−2.79, 95%-CI (−5.42, −0.18)]. When comparing subgroups ± chemotherapy prior to PET, TLR of pancreatic cancers and TLR of peritoneal carcinomatoses were significantly different. At 45 min p.i., the highest tumor-to-backround (TBR) was observed.Conclusion68Ga-Trivehexin is suitable for imaging of αvβ6-integrin expression in pancreatic cancer due to its ability to distinguish primary carcinoma and metastases from background tissue.

Value of [68Ga]Ga-NYM046 PET/CT, in Comparison with 18F-FDG PET/CT, for Diagnosis of Clear Cell Renal Cell Carcinoma.

This study aimed to investigate the diagnostic efficacy of [68Ga]Ga-NYM046 PET/CT in animal models and patients with clear cell renal cell carcinoma (ccRCC) and to compare its performance with that of 18F-FDG PET/CT. Methods: The invivo biodistribution of [68Ga]Ga-NYM046 was evaluated in mice bearing OS-RC-2 xenografts. Twelve patients with ccRCC were included in the study; all completed paired [68Ga]Ga-NYM046 PET/CT and 18F-FDG PET/CT. The diagnostic efficacies of these 2 PET tracers were compared. Moreover, the positive rate of carbonic anhydrase IX in the pathologic tissue sections was compared with the SUVmax obtained by PET/CT. Results: The tumor accumulation of [68Ga]Ga-NYM046 at 1 h after injection in OS-RC-2 xenograft tumor models was 7.21 ± 2.39 injected dose per gram of tissue. Apart from tumors, the kidney and stomach showed high-uptake distributions. In total, 9 primary tumors, 96 involved lymph nodes, and 147 distant metastases in 12 patients were evaluated using [68Ga]Ga-NYM046 and 18F-FDG PET/CT. Compared with 18F-FDG PET/CT, [68Ga]Ga-NYM046 PET/CT detected more primary tumors (9 vs. 1), involved lymph nodes (95 vs. 92), and distant metastases (137 vs. 127). In quantitative analysis, the primary tumors' SUVmax (median, 13.5 vs. 2.4; z = -2.668, P = 0.008) was significantly higher in [68Ga]Ga-NYM046 PET/CT. Conversely, the involved lymph nodes' SUVmax (median, 5.9 vs. 7.6; z = -3.236, P = 0.001) was higher in 18F-FDG PET/CT. No significant differences were found for distant metastases (median SUVmax, 5.0 vs. 5.0; z = -0.381, P = 0.703). Higher [68Ga]Ga-NYM046 uptake in primary tumors corresponded to higher expression of carbonic anhydrase IX, with an R 2 value of 0.8274. Conclusion: [68Ga]Ga-NYM046 PET/CT offers a viable strategy for detecting primary tumors, involved lymph nodes, and distant metastases in patients with ccRCC.

Automated radiofluorination of HER2 single domain antibody: the road towards the clinical translation of [18F]FB-HER2 sdAb.

With the next generation of Human Epidermal Growth Factor Receptor 2 (HER2) -targeting therapies, such as antibody-drug conjugates, showing benefit in "HER2 low" and even "HER2 ultralow" patients, the need for novel methods to quantify HER2 expression accurately becomes even more important for clinical decision making. A HER2 PET/CT imaging assessment could evaluate HER2 positive disease locations while improving patient care, reducing the need for invasive biopsies. A single-domain antibody (sdAb)-based PET tracer could combine the high specificity of sdAbs with short-lived radionuclides such as fluorine-18 (18F) and gallium-68 (68Ga). SdAb-based PET tracers have clinically been used via a 68Ga-chelator approach. However, the distribution of 68Ga-labelled pharmaceuticals to peripheral PET centres is more challenging to organize due to the short half-life of 68Ga, most certainly when the available activity is limited by a generator. Cyclotron produced 68Ga has removed this limitation. Distribution of 18F-labelled pharmaceuticals remains less challenging due to its slightly longer half-life, and radiofluorination of sdAbs via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) has shown to be a promising strategy for developing sdAb-based PET tracers. Although [18F]SFB automation has been reported, automating protein conjugation proves challenging. Herein we report the fully automated, cartridge-based production of [18F]FB-HER2 sdAb on a single synthesis module. [18F]FB-HER2 sdAb (> 6GBq) was obtained after a fully automated production (95min), with a RCP > 95%, apparent molar activity > 20GBq/µmol and decay-corrected radiochemical yield (RCY d.c.) of 14 ± 2% (n = 4). Further upscaling amounted to production batches of 16GBq with an apparent molar activity > 40GBq/µmol and RCY d.c. of 8 ± 1% (n = 4). Ex vivo biodistribution and PET imaging showed specific HER2-positive tumour targeting and low kidney retention. The [18F]FB-HER2 sdAb tracer was produced with clinically relevant activities using a fully automated production method. The automated production method was designed to ease the translation to the clinic and has the potential to be used not only in mono-centre but also multi-centre clinical trials with one central production site. [18F]FB-HER2 sdAb showed a favourable biodistribution pattern and could be a valuable alternative to 68Ga-labelled sdAb-based PET tracers in the clinic.

Selecting Targets for Molecular Imaging of Gastric Cancer: An Immunohistochemical Evaluation.

Tumor-targeted positron emission tomography (PET) and fluorescence-guided surgery (FGS) could address current challenges in pre- and intraoperative imaging of gastric cancer. Adequate selection of molecular imaging targets remains crucial for successful tumor visualization. This study evaluated the potential of integrin αvβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and human epidermal growth factor receptor-2 (HER2) for molecular imaging of primary gastric cancer, as well as lymph node and distant metastases. Expression of αvβ6, CEACAM5, EGFR, EpCAM and HER2 was determined using immunohistochemistry in human tissue specimens of primary gastric adenocarcinoma, healthy surrounding stomach, esophageal and duodenal tissue, tumor-positive and tumor-negative lymph nodes, and distant metastases, followed by quantification using the total immunostaining score (TIS). Positive biomarker expression in primary gastric tumors was observed in 86% for αvβ6, 72% for CEACAM5, 77% for EGFR, 93% for EpCAM and 71% for HER2. Tumor expression of CEACAM5, EGFR and EpCAM was higher compared to healthy stomach tissue expression, while this was not the case for αvβ6 and HER2. Tumor-positive lymph nodes could be distinguished from tumor-negative lymph nodes, with accuracy ranging from 82 to 93% between biomarkers. CEACAM5, EGFR and EpCAM were abundantly expressed on distant metastases, with expression in 88-95% of tissue specimens. Our findings show that CEACAM5, EGFR and EpCAM are promising targets for molecular imaging of primary gastric cancer, as well as visualization of both lymph node and distant metastases. Further clinical evaluation of PET and FGS tracers targeting these antigens is warranted.

11C]PS13 Demonstrates Pharmacologically Selective and Substantial Binding to Cyclooxygenase-1 in the Human Brain.

Our laboratory recently developed [11C]PS13 as a PET radioligand to selectively measure cyclooxygenase-1 (COX-1). The cyclooxygenase enzyme family converts arachidonic acid into prostaglandins and thromboxanes, which mediate inflammation. The total brain uptake of [11C]PS13, which is composed of both specific binding and background uptake, can be accurately quantified with gold standard methods of compartmental modeling. This study sought to quantify the specific binding of [11C]PS13 to COX-1 in healthy human brain using scans performed with arterial input function at baseline and after blockade by the COX-1-selective inhibitor ketoprofen. Methods: Eight healthy volunteers underwent two 90-min [11C]PS13 PET scans with radiometabolite-corrected arterial input function, at baseline and about 2 h after oral administration of ketoprofen (75 mg). Results: Two-tissue compartment modeling effectively identified the total uptake of radioactivity in the brain (as distribution volume), showing the highest densities in the hippocampus, the occipital cortex, and the banks of the central sulcus. All brain regions exhibited displaceable and specific binding, and thus none could be used as a reference region. Ketoprofen blocked approximately 84% of the binding sites on COX-1 in the whole brain. After full occupancy was extrapolated, the average whole-brain values of [11C]PS13 were 1.6 ± 0.8 mL·cm-3 for specific uptake, 1.7 ± 0.6 mL·cm-3 for background uptake, and 1.1 ± 0.5 for the specific-to-background ratio. The hippocampus had the highest specific-to-background ratio value of 2.7 ± 0.9. Conclusion: [11C]PS13 exhibited high specific binding to COX-1 in the human brain, but its quantification requires arterial blood sampling.

Clinical applications of fibroblast activation protein inhibitor positron emission tomography (FAPI-PET)

AbstractThe discovery of fibroblast activation protein inhibitor positron emission tomography (FAPI-PET) has paved the way for a new class of PET tracers that target the tumor microenvironment (TME) rather than the tumor itself. Although 18F-fluorodeoxyglucose (FDG) is the most common PET tracer used in clinical imaging of cancer, multiple studies have now shown that the family of FAP ligands commonly outperform FDG in detecting cancers, especially those known to have lower uptake on FDG-PET. Moreover, FAPI-PET will have applications in benign fibrotic or inflammatory conditions. Thus, even while new FAPI-PET tracers are in development and applications are yet to enter clinical guidelines, a significant body of literature has emerged on FAPI-PET, suggesting it will have important clinical roles. This article summarizes the current state of clinical FAPI-PET imaging as well as potential uses as a theranostic agent.

Triflyl [18F]Fluoride as a Solution for Base-sensitive Late-stage Nucleophilic Aromatic 18F-Fluorination Reactions.

Fluorine-18 is the predominant radionuclide used to label Positron Emission Tomography (PET) tracers. One outstanding challenge in nucleophilic aromatic radiofluorination reactions is the sensitivity of precursors and catalysts for basic reaction conditions, which are necessary for the work-up of [18F]fluoride, resulting in limited reproducibility. Triflyl [18F]fluoride is a new [18F]fluoride source that allows freedom in choice of type and amounts of base and cryptand. The aim of the current work is to explore the scope and limitations of triflyl [18F]fluoride in the late-stage nucleophilic aromatic 18F-fluorination of various functionalized precursors, exploring reduced amounts of base and cryptand. The assessment allowed for the application of this new nucleophilic [18F]fluoride reagent to the successful radiosynthesis of boron, stannane, hypervalent iodonium ylide and phenol substrates bearing electron-deficient, -neutral and -rich functional groups as well as the clinically relevant PET tracers [18F]FPEB, [18F]mFBG and [18F]SynVesT-1.

Immuno-PET Imaging of CD93 Expression with 64Cu-Radiolabeled NOTA-mCD93 ([64Cu]Cu-NOTA-mCD93) and Insulin-Like Growth Factor Binding Protein 7 ([64Cu]Cu-NOTA-IGFBP7).

CD93 is overexpressed in multiple solid tumor types, serving as a novel target for antiangiogenic therapy. The goal of this study was to develop a 64Cu-based positron emission tomography (PET) tracer for noninvasive imaging of CD93 expression. Antimouse-CD93 mAb (mCD93) and the CD93 ligand IGFBP7 were conjugated to a bifunctional chelator, p-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-NOTA) and labeled with 64Cu. To evaluate the pharmacokinetic properties and tumor-targeting efficacy of [64Cu]Cu-NOTA-mCD93 and [64Cu]Cu-NOTA-IGFBP7, PET imaging and biodistribution were performed on both 4T1 murine breast tumor-bearing mice and MDA-MB-231 human breast tumor-bearing mice. The tumor model HT1080-FAP, which does not overexpress CD93, was used as a negative control. Fluorescent immunostaining was conducted on different tissues to correlate radiotracer uptake with CD93 expression. 64Cu-labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the in vivo performance of [64Cu]Cu-NOTA-IGFBP7 was superior to that of [64Cu]Cu-NOTA-mCD93, and that the tracer [64Cu]Cu-NOTA-IGFBP7 exhibited elevated tumor uptake values and excellent tumor retention in MDA-MB-231 mice, rather than in 4T1 murine mice. The MDA-MB-231 tumor uptake of [64Cu]Cu-NOTA-IGFBP7 was 2.85 ± 0.15, 3.69 ± 0.60, 6.91 ± 0.88, and 6.35 ± 0.55%ID/g at 1, 4, 24, and 48 h p.i., respectively, which were significantly higher than that in the CD93-negative HT1080-FAP tumor (0.73 ± 0.15, 0.97 ± 0.31, 1.00 ± 0.07, and 1.02 ± 0.11%ID/g, respectively). The significant difference between positive and negative tumors indicated [64Cu]Cu-NOTA-IGFBP7 was specifically binding to CD93. Biodistribution data as measured by gamma counting were consistent with the PET analysis. Ex vivo histology further confirmed the high CD93 expression on MDA-MB-231 tumor tissues. Herein, we prepared two novel radiotracers, [64Cu]Cu-NOTA-mCD93 and [64Cu]Cu-NOTA-IGFBP7, for the first immune-PET imaging of CD93 expression. Our results suggest that [64Cu]Cu-NOTA-IGFBP7 is a more potential radiotracer for visualizing angiogenesis due to its sensitive, persistent, and CD93-specific characteristics.

Abstract 4136234: Increased Reactive Oxygen Species using [18F]ROStrace PET and Dihydroethidium Staining in Myocardial Infarction Reperfusion injury

Introduction: Patients with reperfusion injury following myocardial infarction (MI) are at a higher risk of heart failure. Reactive oxygen species (ROS) activity can further damage cardiomyocytes and compromise heart function. Imaging methods are needed to assess ROS in vivo to investigate targeted adjunctive therapies. Our group developed a novel ROS-activated PET radiotracer [18F]ROStrace to fill this gap. In this study, we measured [18F]ROStrace fractional uptake rate (FUR) and for the first time compared it with histologic assessment of infarct and myocardium specimens. We hypothesized that [18F]ROStrace FUR was increased in the infarct and that [18F]ROStrace FUR was supported by [18F]ROStrace analogue dihydroethidium (DHE) staining. Methods: MI was induced in five swine, followed by reperfusion after 90 minutes. In vivo LGE CMR imaging and [18F]ROStrace and [82]Rb PET were performed at ~3-4 days after infarction. A terminal procedure was then performed. DHE and 4′,6-diamidino-2-phenylindole (DAPI) staining was done. Two swine received injections of DHE in the right and left coronary arteries to assess ROS. ROS activity was determined from [18F]ROStrace by computing the [82]Rb myocardial blood flow (MBF) corrected FUR. The linear relationship between infarct and MVO size, and MBF-corrected [18F]ROStrace FUR were calculated using the Pearson’s r. Results: There was a strong and positive correlation between infarct and MVO size (r=0.9, p=0.04). The MBF-corrected ROStrace FUR at baseline was 0.07±0.06 ml/g, infarct was 0.15 ± 0.05 ml/g, and remote was 0.09 ± 0.05 ml/g. We observed a significant difference between ROS in the infarct and remote region (p=0.01), which is also seen in the increased DHE staining in the infarct. We also observed increased DAPI staining in the infarct region compared to free wall due to the presence of inflammatory cells, thus increasing the number of nuclei. Conclusion: [18F]ROStrace is increased in the infarct during the subacute period post-MI compared to healthy and remote myocardium and supported by histological assessment. This work may lead to the use of in vivo [18F]ROStrace PET to support development of therapeutic strategies targeting ROS to reduce MI.

PET Imaging in Alzheimer Disease: Pathology and Research Insights for Technologists.

Alzheimer disease (AD) is the sixth leading cause of death in the United States and is projected to affect over 13 million people by the year 2060. Although there is currently no cure for AD, disease-modifying treatments that target amyloid plaques have recently been approved for use. The advent of PET tracers that can reliably detect the presence of cortical amyloid plaques and tau pathologies has allowed researchers and clinicians to identify individuals who have pathologic markers of AD before the onset of cognitive decline. Although these tracers have been widely used in research settings for some time, they are now on the verge of being used to aid clinicians in the differential diagnosis of AD. As the use of these tracers increases, technologists will need to be educated on the best practices and potential problems they may encounter in their clinical populations. This article will review the available tracers for amyloid and tau PET scans and educate technologists about the most important practices and procedures that can be implemented to ensure patient safety and the capture of high-quality scans.

NIMG-80. IMPACT OF KETOGENIC DIET ON MOLECULAR METABOLIC IMAGING WITH [18F]FDG AND [18F]DASA-23 POSITRON EMISSION TOMOGRAPHY IN A PATIENT WITH GLIOBLASTOMA

Abstract The standard-of-care for neuroimaging in patients with glioblastoma is contrast-enhanced MRI, which does not provide tumor metabolism information. Although [18F]FDG PET is used to image tumor metabolism in many solid organ cancers, it has limited benefit in atients with brain tumors due to the high level of glucose uptake in normal brain cells. [18F]DASA-23 is a novel PET radiotracer that assesses the levels of pyruvate kinase M2 (PKM2), a protein highly expressed in cancer cells, which undergo aberrant glycolysis. Despite [18F]DASA-23 having a higher tumor-to-background ratio (TBR) of standardized uptake values (SUVs) in the brain compared to [18F]FDG, both may be susceptible to altered carbohydrate metabolism in the setting of a ketogenic diet (KD). We report the case of a patient with glioblastoma on a KD, whose [18F]FDG and [18F]DASA-23 PET brain scans were limited in identifying disease progression (PD). Background was defined as the white matter contralateral to the tumor, at the level of the centrum semiovale, for TBR of SUVmax. A 39-year-old man was diagnosed with right temporal glioblastoma after previous diagnoses of grade 2 gliofibrillary oligodendroglioma (age 20) and grade 3 anaplastic oligodendroglioma (age 22). He began a KD after the glioblastoma diagnosis. 21 months later, TBR on [18F]DASA-23 PET was 1.38. One month later, surveillance brain MRI showed PD. Ten days later, TBR on [18F]FDG PET was 1.03. The patient died 15 months later. Despite MRI-based PD, the TBR of each radiotracer was not markedly elevated, although the [18F]DASA-23 TBR 1-month pre-PD was 34% greater than the [18F]FDG PET TBR 10-days post-PD. This may suggest a limitation of metabolic imaging by PET in the setting of a KD, and provide an opportunity to develop novel PET radiotracers that are not susceptible to the patient’s diet.

NIMG-10. THE ROLE OF FIBROBLAST ACTIVATION PROTEIN IN GLIOBLASTOMA AND GLIOSARCOMA – A COMPARISON OF TISSUE, 68GA-FAPI-46 POSITRON EMISSION TOMOGRAPHY AND SURVIVAL DATA

Abstract BACKGROUND Despite their unique histological features,gliosarcomas belong to the group of glioblastomas and are treated according to the same standards. Fibroblast-activation-protein(FAP) is a component of a tumor-specific subpopulation of fibroblasts that play a critical role in tumor growth and invasion.However,the prognostic impact of FAP in glioblastoma and gliosarcoma is unclear. METHODS In a retrospective analysis,patients diagnosed with glioblastoma without sarcomatous differentiation and gliosarcoma were enrolled.Histological examination was performed using immunohistochemical FAP-staining and quantitative analysis with a standardized FAP-score.In a subset of patients,FAPI46-PET has been performed.The SUV-values are planned to be correlated with FAP-expression in the tumor tissue.Data obtained from immunohistochemical analysis and SUV-values are planned to be brought into perspective with clinically relevant prognostic factors,including survival estimates. RESULTS We enrolled 61 patients,including 13 diagnosed with gliosarcoma.Our analysis revealed that gliosarcomas exhibit significantly higher FAP-expression (median FAP-score: 3) compared to glioblastomas without sarcomatous differentiation (median FAP-score: 0.5, p<0.0001),where FAP was predominantly observed in the perivascular space.In gliosarcomas,FAP was also expressed by neoplastic cells.Moreover,a significant relationship was established between the immunohistochemical FAP-scores and the SUVmean and SUVpeak values on PET,suggesting that the PET tracer uptake accurately reflects the tumor’s FAP-expression.However,the differential expression of FAP suggests its potential as both a diagnostic marker and a therapeutic target.This hypothesis is further supported by the application of 68Ga-FAPI-46-PET in a 66-year-old female patient with recurrent gliosarcoma,alongside immunohistochemical analysis of tumor tissue.Both methods identified elevated FAP-expression and uptake,underscoring the feasibility of FAP as a target for nuclear medicine therapies in brain tumors. CONCLUSIONS Our study establishes a significant correlation between SUVmean/SUVpeak in 68Ga-FAPI-46 PET scans and FAP-expression in glioblastoma.Gliosarcomas express significantly more FAP than other glioblastomas. These insights suggest FAP’s potential as a theranostic target.We plan to investigate the effectiveness of FAP-specific tracers in treating recurrent gliosarcoma,aiming to open new therapeutic avenues.

BIOM-44.18F-DOPA-PET THRESHOLDS FOR BOTH NEWLY DIAGNOSED AND RECURRENT ASTROCYTOMA USING PATHOLOGICAL GROUPING OF SPATIALLY CORRELATED BIOPSIES

Abstract BACKGROUND Glioma radiotherapy planning requires accurate tumor delineation. While T1- contrast-enhanced-MRI (T1-CE-MRI) is the standard, due to blood-brain-barrier breakdown dependencies, T1-CE-MRI fails to reflect the extent of glioma. Studies using amino acid PET tracers report glioma uptake up to 3cm-4cm beyond T1-CE. In this study, amino acid tracer 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) uptake was correlated with histopathological features to determine tumor thresholds. METHODS Using registered 18F-DOPA-PET and T1-CE-MRI images in the Stealth Neuronavigation system targeting concordant and discordant regions, 181 stereotactic biopsy samples (newly-diagnosed=74; recurrent=107) were obtained from 59 enrolled astrocytoma patients across two prospective phase II clinical trials between 2010-2019. An experienced neuropathologist reviewed each sample with hematoxylin and eosin stain and assigned an alphanumeric score: mitotic activity (0=no tumor; 1=no mitosis; 2=few/scattered mitosis; 3=frequent mitosis) and cellular density (A=<25%; B=25%-50%; C=50%-75%; D=>75%). Samples assigned 1C-1D, 2B-2D, or 3A-3D were categorized as histopathological high-score (aggressive disease), remaining samples as low-score. Relative mean (rFDOPA_mean) tumor-to-background uptake ratios were computed for 5mm uniformly expanded volumes from each Stealth biopsy coordinate using the crescent and wedge normalization methods. Relative uptake was compared overall and separately within newly-diagnosed/recurrent disease subgroups. An optimal rFDOPA_mean threshold to delineate high- from low-score was determined using the maximal Youden index of ROC curves. RESULTS Overall, high-score samples (n=116) had higher median (IQR) rFDOPA_mean uptake than low-score samples (n=65): high-score rFDOPA:mean=1.70(1.16-2.26), low-score rFDOPA:mean=1.16(0.83-1.49), Kruskal-Wallis p<0.001. The uptake difference between high- vs. low-score samples was observed within newly-diagnosed and recurrent subgroups, but was only significant for newly-diagnosed (p<0.001). For newly-diagnosed, an rFDOPA:mean=1.49 cutoff between high- and low-score groups shows 69% accuracy, 63% sensitivity, 80% specificity (AUC=0.782). Using the wedge normalization method, rFDOPA_mean values were 0.2 higher than crescent method values. CONCLUSIONS This work presents histologically verified 18F-DOPA-PET thresholds for aggressive disease in newly-diagnosed astrocytoma patients. Separate thresholds will need to be determined for recurrent glioma patients.

α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor density underlies intraregional and interregional functional centrality

Local and global functional connectivity densities (lFCD and gFCD, respectively), derived from functional magnetic resonance imaging (fMRI) data, represent the degree of functional centrality within local and global brain networks. While these methods are well-established for mapping brain connectivity, the molecular and synaptic foundations of these connectivity patterns remain unclear. Glutamate, the principal excitatory neurotransmitter in the brain, plays a key role in these processes. Among its receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is crucial for neurotransmission, particularly in cognitive functions such as learning and memory. This study aimed to examine the association of the AMPAR density and FCD metrics of intraregional and interregional functional centrality. Using [11C]K-2, a positron emission tomography (PET) tracer specific for AMPARs, we measured AMPAR density in the brains of 35 healthy participants. Our findings revealed a strong positive correlation between AMPAR density and both lFCD and gFCD-lFCD across the entire brain. This correlation was especially notable in key regions such as the anterior cingulate cortex, posterior cingulate cortex, pre-subgenual frontal cortex, Default Mode Network, and Visual Network. These results highlight that postsynaptic AMPARs significantly contribute to both local and global functional connectivity in the brain, particularly in network hub regions. This study provides valuable insights into the molecular and synaptic underpinnings of brain functional connectomes.

Bexotegrast Shows Dose-dependent Integrin αvβ6 Receptor Occupancy in Lungs of Participants with Idiopathic Pulmonary Fibrosis: A Phase 2, Open-Label Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-beta (TGF-β) activation mediated by αv integrins is central to the pathogenesis of IPF. Bexotegrast (PLN 74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an αvβ6-specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives: This Phase 2 study (NCT04072315) evaluated αvβ6 receptor occupancy in the lung, as assessed by changes from baseline in αvβ6 PET tracer uptake, following single dose administration of bexotegrast to participants with IPF. Methods: In this open-label, single-center, single-arm study, adults with IPF received up to 2 single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET/CT scan was conducted following administration of an αvβ6-specific PET probe ([18F]FP-R01-MG-F2). αvβ6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake following bexotegrast. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results: Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution (VT) values decreased in a dose- and concentration-dependent manner. The VT data fit a simple saturation model, producing an unbound bexotegrast EC50 estimate of 3.32 ng/mL. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% following single 60, 80, 120, 240, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions: Dose- and concentration-dependent αvβ6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160 to 320 mg dosing to evaluate efficacy in clinical trials of IPF. Trial registration number: NCT04072315 Primary source of funding: Pliant Therapeutics, Inc. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Discovery of 18F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

The histamine subtype 3 (H3) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H3 receptor. In this study, we synthesized and evaluated the binding effects of [18F]H3-2404 and [18F]H3-2405 by modifying the structure of AZD5213, a selective H3 antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [18F]H3-2404 and [18F]H3-2405 are unsuitable as PET tracers for brain imaging of the H3 receptor, this study provides a valuable attempt for optimizing 18F labeled radiotracers based on AZD5213.

Synthesis, preclinical assessment, and first-in-human study of [18F]d4-FET for brain tumor imaging.

Tumor-to-background ratio (TBR) is a critical metric in oncologic PET imaging. This study aims to enhance the TBR of [18F]FET in brain tumor imaging by substituting deuterium ("D") for hydrogen ("H"), thereby improving the diagnostic sensitivity and accuracy. [18F]d4-FET was synthesised by two automated radiochemistry modules. Biodistribution studies and imaging efficacy were evaluated in vivo and ex vivo in rodent models, while metabolic stability and radiation dosimetry were assessed in non-human primates. Additionally, preliminary imaging evaluations were carried out in five brain tumor patients: three glioma patients underwent imaging with both [18F]d4-FET and [18F]FET, and two patients with brain metastases were imaged using [18F]d4-FET and [18F]FDG. [18F]d4-FET demonstrated high radiochemical purity and yield. PET/MRIin rodent models demonstrated superior TBR for [18F]d4-FET compared to [18F]FET, and autoradiography showed tumor margins that correlated well with pathological extents. Studies in cynomolgus monkeys indicated comparable in vivo stability and effective dose with [18F]FET. In glioma patients, [18F]d4-FET showed enhanced TBR, while in patients with brain metastases, [18F]d4-FET displayed superior lesion delineation compared to [18F]FDG, especially in smaller metastatic sites. We successfully synthesized the novel PET radiotracer [18F]d4-FET, which retains the advantageous properties of [18F]FET while potentially enhancing TBR for glioma imaging. Preliminary studies indicate excellent stability, efficacy, and sensitivity of [18F]d4-FET, suggesting its potential in clinical evaluations of brain tumors. ChiCTR2400081576, registration date: 2024-03-05, https://www.chictr.org.cn/bin/project/edit?pid=206162.

Synthesis and preclinical evaluation of [18F]AlF-NODA-MP-C6-CTHRSSVVC as a PET tracer for CD163-positive tumor-infiltrating macrophages

Positron emission tomography (PET) can provide information about tumor-associated macrophage (TAM) infiltration, as long as a suitable tracer is available. This study aimed to evaluate the radiolabeled peptide [18F]AlF-NODA-MP-C6-CTHRSSVVC as a potential PET tracer for imaging of the CD163 receptor, which is expressed on M2-type tumor-associated macrophages. The conjugated peptide NODA-MP-C6-CTHRSSVVC was labeled with aluminum [18F]fluoride. Tracer binding and its biodistribution were evaluated in an in vitro binding assay and in healthy BALB/c mice, respectively. In addition, different treatments with cyclophosphamide in tumor-bearing mice were used to assess whether the tracer could detect differences in CD163 expression caused by differential TAM infiltration. After 7 days of treatment, animals were injected with [18F]AlF-NODA-MP-C6-CTHRSSVVC, and a 60-min dynamic PET scan was performed, followed by an ex vivo biodistribution study. [18F]AlF-NODA-MP-C6-CTHRSSVVC was prepared in 23 ± 6 % radiochemical yield and showed approximately 50 % of specific receptor-mediated binding in an in vitro binding assay on human CD163-expressing tissue homogenates. No CD163-mediated binding of [18F]AlF-NODA-MP-C6-CTHRSSVVC was detected by PET under normal physiological conditions in healthy BALB/c mice. On the other hand, CD163-positive xenograft tumors were clearly visualized with PET and a positive correlation was found between CD163 levels and the [18F]AlF-NODA-MP-C6-CTHRSSVVC tumor-to-muscle ratio (TMR) obtained from the PET images (Pearson r = 0.76, p = 0.002). No significant differences in the CD163 protein level and in the tracer uptake between treatment groups were found in the tumors. Taken together, [18F]AlF-NODA-MP-C6-CTHRSSVVC appears a promising candidate PET tracer for M2-type TAM, as it binds specifically to CD163 in vitro and its tumor uptake correlates well with CD163 expression in vivo.

Preclinical in vitro and in vivo evaluation of [11C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates.

This paper describes the preclinical validation of the radioligand [11C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α2CR) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α2CR. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [3H]ORM-13070. BAY 292 bound to the same binding site as [3H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α2CR. In non-human primates in vivo, [11C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α2CR. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC50 for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [11C]ORM-13070 as a PET-radioligand for the study of α2CR in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292.

Different PSMA Radiopharmaceuticals: A Comparative Study of [18F]F-PSMA-1007, [18F]F-JK-PSMA-7, and [99mTc]Tc-PSMA-I&S in the Skeletal System

Background: Numerous PSMA-based tracers are used for diagnostic prostate cancer imaging, but comprehensive comparisons between multiple ligands are lacking. This study aimed to compare physiological skeletal uptake and tracer uptake in commonly recommended PSMA reference regions across three different PSMA ligands in prostate cancer patients. Methods: A total of 281 prostate cancer patients were included. Using PET and SPECT imaging, target volumes of interest were defined via a semiautomatic method, and standardized uptake values (SUV) were calculated for the skeletal system and reference regions (liver, spleen, parotid gland, and blood pool). Results: Significant differences in SUV uptake were observed, with [18F]F-PSMA-1007 showing higher SUV values in the skeletal system. The parotid gland displayed the highest variability in uptake, while the blood pool and liver exhibited more homogeneous uptake across patients. Conclusions: While radioligands behave similarly in bone regions, there are notable differences in SUV patterns, particularly for PSMA-1007, which showed higher bone uptake. Parotid gland uptake variability suggests a reconsideration of its suitability as a reference region, while the liver, spleen, and blood pool showed more consistent uptake. During comparison, the technetium-labeled SPECT ligand proved as similarly effective as the two PET ligands for diagnostic imaging.