PET Tracer Research Articles

PET Quantification in Healthy Humans of Cyclooxygenase-2, a Potential Biomarker of Neuroinflammation.

Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [11C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)pyrimidin-4-amine ([11C]MC1) to detect COX-2 density in a healthy human brain. Methods: The specificity of [11C]MC1 was confirmed using lipopolysaccharide-injected rats and transgenic mice expressing the human COX-2 gene, with 120-min baseline and blocked scans using COX-1 and COX-2 selective agents. Twenty-seven healthy participants were injected with [11C]MC1. Ten of these participants received 2 PET scans: a baseline study followed by blockade with celecoxib (600 mg orally), a preferential COX-2 inhibitor. Seventeen participants underwent test-retest imaging. All scans included concurrent arterial sampling. The tissue-to-plasma ratio at equilibrium (i.e., total distribution volume) was determined using a 2-tissue compartment model (2TCM). Results: In humanized transgenic COX-2 mice, 70%-90% of [11C]MC1 brain uptake was blocked by nonradioactive MC1 and celecoxib (a COX-2 selective inhibitor) but not by PS13 (a COX-1 selective inhibitor), thereby confirming specific binding to human COX-2. Radioactivity in the human brain peaked at a concentration of about 4.0 SUV, indicating good passage through the blood-brain barrier. Values for the total distribution volume achieved stability after 80 min, indicating no radiometabolite contamination. Celecoxib reduced radioligand binding in neocortical areas by 25% but had little or no effect in subcortical regions and the cerebellum, which correlated with COX-2 messenger RNA expression levels. Binding site occupancy by celecoxib was virtually complete, as determined by the Lassen plots. Test-retest reliability was moderate (intraclass correlation coefficient, 0.65) but had relatively large variability (absolute retest variability, 20%). Reference tissue methods yielded results comparable to those of 2TCM but reduced retest variability by up to 75% and reduced intersubject variability (coefficient of variation) by about half. Thus, compared with 2TCM, which requires arterial blood, the reference tissue method is expected to significantly reduce the sample sizes required to detect statistically significant differences between groups. Conclusion: [11C]MC1 has adequate sensitivity to measure the low density of COX-2 in a healthy human brain, suggesting it can also quantify the COX-2 elevations expected in human disorders associated with neuroinflammation.

Autoradiography of Intracerebral Tumours in the Chick Embryo Model: A Feasibility Study Using Different PET Tracers.

In addition to rodent models, the chick embryo model has gained attention for radiotracer evaluation. Previous studies have investigated tumours on the chorioallantoic membrane (CAM), but its value for radiotracer imaging of intracerebral tumours has yet to be demonstrated. Human U87 glioblastoma cells and U87-IDH1 mutant glioma cells were implanted into the brains of chick embryos at developmental day 5. After 12-14days of tumour growth, blood-brain-barrier integrity was evaluated in vivo using MRI contrast enhancement or ex vivo with Evans blue dye. The tracers O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) (n = 5), 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine ([18F]FDOPA) (n = 3), or [68Ga] labelled quinoline-based small molecule fibroblast activation protein inhibitor ([68Ga]FAPI-46) (n = 4) were injected intravenously if solid tumours were detected with MRI. For time-activity curves for [18F]FET, additional micro PET (µPET) was performed. The chick embryos were sacrificed 60min post-injection, and cryosections of the tumour-bearing brains were produced and evaluated with autoradiography and immunohistochemistry. Intracerebral tumours were produced with a 100% success rate in viable chick embryos at the experimental endpoint. However, 52% of chick embryos (n = 85) did not survive the procedure to embryonic development day 20. For the evaluated radiotracers, the tumour-to-brain ratios (TBR) derived from ex vivo autoradiography, as well as the tracer kinetics derived from µPET for intracerebral chick embryo tumours, were comparable to those previously reported in rodents and patients: the TBRmean for [18F]FET was 1.69 ± 0.54 (n = 5), and 3.8 for one hypermetabolic tumour and < 2.0 for two isometabolic tumors using [18F]FDOPA, with a TBRmean of 1.92 ± 1,11 (n = 3). The TBRmean of [68Ga]FAPI-46 for intracerebral chick embryo tumours was 19.13 ± 0.64 (n = 4). An intact blood-tumour barrier was observed in one U87-MG tumour (n = 5). Radiotracer imaging of intracerebral tumours in the chick embryo offers a fast model for the evaluation of radiotracer uptake, accumulation, and kinetics. Our results indicate a high comparability between intracerebral tumour imaging in chick embryos and xenograft rodent models or brain tumour patients.

Radiolabeling and Preliminary In Vivo Evaluation of the Candidate CCR2 Targeting PET Radioligand [11C]AZD2423

Radiolabeling and Preliminary In Vivo Evaluation of the Candidate CCR2 Targeting PET Radioligand [11C]AZD2423

Compartmental modeling for blood flow quantification from dynamic O-water PET images of humans: a systematic review.

Dynamic positron emission tomography (PET) can be used to non-invasively estimate the blood flow of different organs via compartmental modeling. Out of different PET tracers, water labeled with the radioactive O isotope of oxygen (half-life of 2.04min) is freely diffusable, and therefore, very well-suited for blood flow quantification. While the earlier O-water PET research has primarily focused on cerebral or myocardial blood flow quantification, the recent emergence of total-body PET scanners has enabled greater application possibilities for both PET imaging in general and also O-water PET based blood flow quantification in particular. However, to validate new methods, it is necessary to compare them to earlier research. To help in this process, we systematically review 53 articles quantifying blood flow via compartmental modeling. We introduce the articles organized within subcategories of cerebral, myocardial, renal, pulmonary, pancreatic, hepatic, muscle, and tumor blood flow and summarize their results so that they can easily be evaluated in terms of population characteristics of the patients such as age or sex ratio and their potential diagnoses. We compare how both the compartment model used and the potential corrections for arterial blood volume, non-perfusable tissue, spill-over from the heart cavities, and time delay caused while the tracer travels between different areas of interest are generally implemented in the articles. We also analyze the differences in the data pre-processing techniques. According to our results, the estimates of cerebral and tumor blood flow vary considerably more between the articles than those of myocardial blood flow. This might be caused by differences in the model approaches or the study populations. We also note that the choice of the unit for these estimates is quite inconsistent as certain researchers seem to prefer mL/min/g over mL/min/mL even if no weight or density parameter is present in the modeling. We encourage more research on sex- and age-based differences in blood flow estimates and organ-specific blood flow quantification studies for kidneys, lungs, liver, and other important organs besides brain and heart.

Clinical Translation of a Dual-Integrin αvβ3- and CD13-Targeting PET Tracer.

Angiogenesis is essential in the development and progression of tumors. This study aimed to investigate the clinical application of 68Ga-labeled heterodimeric peptide (68Ga-HX01) targeting integrin αvβ3 and CD13 in tumor neovascularization. Six healthy volunteers were recruited to study the biodistribution, pharmacokinetics, and radiation of 68Ga-HX01. Twelve patients with various malignancies were enrolled to seek the preliminary clinical value of 68Ga-HX01. In healthy volunteers, SUVs of each major organ on 68Ga-HX01 PET were measured. The clinical data, lesion numbers, and uptake were recorded in patients. The integrin αvβ3 and CD13 expression of the resected tumors was checked via immunohistochemistry staining. With a mean injected dose of 167.98 ± 26.32 MBq, 68Ga-HX01 was well tolerated and safe without side effects in 6 healthy volunteers. The radiation absorbed effective dose of 68Ga-HX01 was 1.94 × 10-2 mSv/MBq, and the urinary bladder wall held the highest absorbed effective dose (0.15 ± 5.87 × 10-2 mSv/MBq). In 12 patients with various malignancies, 68Ga-HX01 PET could clearly visualize the lesions from the surrounding tissues. The SUVmax values in tumors were significantly higher than those in the surrounding tissues (P < 0.05). A positive correlation trend between tumor SUVmax and semiquantitative integrin αvβ3 and CD13 expression was determined (P < 0.05). For clinical use, 68Ga-HX01 is safe with low radiation absorbed effective dose. It also indicates the efficiency of dual integrin αvβ3 and CD13-targeting PET radiotracer in tumor diagnosis, which may assist in patient prognosis and selecting eligible patients for antiangiogenic therapy.

Imaging Demyelinated Axons After Spinal Cord Injuries with PET Tracer [18F]3F4AP.

Spinal cord injuries (SCIs) often lead to lifelong disability. Among the various types of injuries, incomplete and discomplete injuries, where some axons remain intact, offer potential for recovery. However, demyelination of these spared axons can worsen disability. Demyelination is a reversible phenomenon, and drugs such as 4-aminopyridine (4AP), which target K+ channels in demyelinated axons, show that conduction can be restored. Yet, accurately assessing and monitoring demyelination after SCI remains challenging because of the lack of suitable imaging methods. In this study, we introduce a novel approach using the PET tracer, 3-[18F]fluoro-4-aminopyridine ([18F]3F4AP), specifically targeting K+ channels in demyelinated axons for SCI imaging. Methods: Rats with incomplete contusion injuries were imaged with [18F]3F4AP PET up to 1 mo after injury, followed by further validation of PET imaging results with autoradiography and immunohistochemistry of postmortem spinal cord tissue. A proof-of-concept study in 2 human subjects with incomplete injuries of different severities and etiologies was also performed. Results: [18F]3F4AP PET of SCI rats revealed a more than 2-fold increase in tracer binding highly localized to the injured segment of the cord at 7 d after injury relative to baseline (SUV ratio = 2.49 ± 0.09 for 7 d after injury vs. 1.14 ± 0.10 for baseline), revealing [18F]3F4AP's exceptional sensitivity to injury and its ability to detect temporal changes. Autoradiography, histology, and immunohistochemistry confirmed [18F]3F4AP's targeting of demyelinated axons. In humans, [18F]3F4AP differentiated between a severe and a largely recovered incomplete injury, indicating axonal loss and demyelination, respectively. Moreover, alterations in tracer delivery were evident on dynamic PET images, suggestive of differences in spinal cord blood flow between the injuries. Conclusion: [18F]3F4AP demonstrates efficacy in detecting incomplete SCI in both animal models and humans. The potential for monitoring post-SCI demyelination changes and response to therapy underscores the utility of [18F]3F4AP in advancing our understanding and management of SCI.

Safety, Biodistribution, and Radiation Dosimetry of the 68Ga-Labeled Minigastrin Analog DOTA-MGS5 in Patients with Advanced Medullary Thyroid Cancer and Other Neuroendocrine Tumors.

Several exploratory studies have demonstrated the feasibility of cholecystokinin-2 receptor (CCK2R) targeting in patients with medullary thyroid carcinoma (MTC) and other neuroendocrine tumors (NETs). We report the results of a prospective phase I/IIA pilot study (clinicaltrials.gov NCT06155994) conducted at our center with the 68Ga-labeled peptide analog DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-Phe-NH2 (68Ga-DOTA-MGS5). Methods: Six patients with advanced MTC and 6 patients with gastroenteropancreatic and bronchopulmonary NETs confirmed by previous PET/CT imaging with other PET tracers received a single dose of 180 MBq of 68Ga-DOTA-MGS5. The first 6 patients enrolled in the study were included in the dosimetry evaluation, and safety was assessed in all 12 patients. PET/CT imaging was performed at different time points after injection to perform dosimetric calculations and to determine the optimal imaging time window. In addition, blood and urine samples were collected for pharmacokinetic assessments. Results: The administration of 68Ga-DOTA-MGS5 was well tolerated, with minor adverse drug reactions occurring only in 3 patients. 68Ga-DOTA-MGS5 was cleared rapidly from the blood, with less than 21% of the injected activity present in blood 215 ± 10 min after injection. Tracer elimination occurred mainly through the kidneys, with a cumulative urinary excretion greater than 40% 3 h after injection. A high percentage of intact radiopeptide was confirmed in plasma. The highest absorbed dose was found for the urinary bladder wall, the stomach wall, and the kidneys, with an effective dose of 0.023 ± 0.007 mSv/MBq. The time points of 1 and 2 h after injection proved to be optimal for PET/CT imaging. In the 6 patients included in the dosimetry evaluation, local metastasis was confirmed in 2 patients with advanced MTC, whereas only 1 of 4 patients with gastroenteropancreatic NETs was positive in 68Ga-DOTA-MGS5 PET/CT. Conclusion: Besides confirming the safety of administration, within the phase I part of the prospective clinical trial, an acceptable effective whole-body dose, an overall favorable biodistribution, and the feasibility of cholecystokinin-2 receptor imaging could be shown for 68Ga-DOTA-MGS5.

Patterns of Tau pathology in patients with anti-IgLON5 disease visualized by Florzolotau (18F) PET.

Anti-IgLON5 disease is a rare autoimmune neurological disorder with prominent Tau protein deposits in the brainstem and hypothalamus. The aim of this study was to visualize the in vivo distribution patterns of Tau protein in patients with anti-IgLON5 disease using the second-generation Tau PET tracer, Florzolotau (18F) PET imaging. Patients diagnosed with anti-IgLON5 disease were enrolled consecutively. Age- and sex-matched healthy controls (HCs) were also enrolled. The uptake of Florzolotau (18F) and 18F-FDG was assessed using both visual and semi-quantitative analysis techniques. A total of 10 patients with anti-IgLON5 disease and 40 HCs were included in the study. All ten patients with anti-IgLON5 disease underwent Florzolotau (18F) PET scans, and five of them underwent 18F-FDG PET scans. Twenty HCs underwent Florzolotau (18F) PET scans, and the remaining 20 HCs underwent 18F-FDG PET scans. In patients with anti-IgLON5 disease, significant uptake of Florzolotau (18F) was observed predominantly in the midbrain, pons, cerebellum, caudate, and putamen. This uptake pattern was notably absent in the control group. Moreover, semi-quantitative analysis techniques demonstrated widespread hypometabolism in the cerebral cortex in patients with anti-IgLON5 disease. This study indicates distinct Tau protein deposition patterns in patients with anti-IgLON5 disease, potentially serving as imaging biomarkers.

Gastrin-Releasing Peptide Receptor Targeting PET/CT With 68Ga-NOTA-RM26 in the Assessment of Glioma and Combined Multiregional Biopsies.

The aim of this study was to investigate the value of 68Ga-NOTA-RM26 (68Ga-RM26), a gastrin-releasing peptide receptor-targeting antagonist labeled with the radionuclide 68Ga, in the diagnosis of high-grade gliomas and in combination with multiregional biopsies using PET/CT. After institutional review board approval and informed consent, a total of 35 patients with suspected glioma lesions were enrolled in this study. All patients underwent 68Ga-RM26 PET/CT scans within 2 weeks before surgery. There were 8 grade II gliomas, 6 grade III gliomas, and 18 grade IV gliomas in a total of 32 glioma lesions. 68Ga-RM26 PET/CT diagnosed 74.4% of lesions (27/32) of all glioma tumor types, and almost all high-grade gliomas were successfully diagnosed (23/24, 95.8%). Among the 9 negative glioma lesions, there were 8 low-grade gliomas (grade II). There was a significantly higher SUVmax, SUVmean, and the lesion-to-background ratio (T/B ratio) in high-grade gliomas compared with low-grade gliomas (P < 0.001). In addition, there was a high correlation between the immunohistochemical staining score of gliomas and parameters (SUVmax, SUVmean, and T/B ratio) on 68Ga-RM26 PET/CT (P < 0.001), and verified by immunohistochemical staining on multiple-point samples of glioma lesions guided by 68Ga-RM26 PET/CT. 68Ga-RM26 could noninvasively diagnose high-grade gliomas and be a promising PET tracer for predicting glioma grading before surgery. This pilot study indicated that the uptake of 68Ga-RM26 correlates with WHO grade in glioma, and preoperative 68Ga-RM26 PET/CT may be helpful to guide multiple-point biopsy of gliomas.

Nuclear Medicine and Molecular Imaging in Urothelial Cancer: Current Status and Future Directions.

Background: The role of molecular imaging in urothelial cancer is less defined than other cancers, and its utility remains controversial due to limitations such as high urinary tracer excretion, complicating primary tumour assessment in the bladder and upper urinary tract. This review explores the current landscape of PET imaging in the clinical management of urothelial cancer, with a special emphasis on potential future advancements including emerging novel non-18F FDG PET agents, PET radiopharmaceuticals, and PET-MRI applications. Methods: We conducted a comprehensive literature search in the PubMed database, using keywords such as "PET", "PET-CT", "PET-MRI", "FDG PET", "Urothelial Cancer", and "Theranostics". Studies were screened for relevance, focusing on imaging modalities and advances in PET tracers for urothelial carcinoma. Non-English language, off-topic papers, and case reports were excluded, resulting in 80 articles being selected for discussion. Results: 18F FDG PET-CT has demonstrated superior sensitivity over conventional imaging, such as contrast-enhanced CT and MRI, for detecting lymph node metastasis and distant disease. Despite these advantages, FDG PET-CT is limited for T-staging of primary urothelial tumours due to high urinary excretion of the tracer. Emerging evidence supports the role of PETC-CT in assessing response to neoadjuvant chemotherapy and in identifying recurrence, with a high diagnostic accuracy reported in several studies. Novel PET tracers, such as 68Ga-labelled FAPI, have shown promising results in targeting cancer-associated fibroblasts, providing higher tumour-to-background ratios and detecting lesions missed by traditional imaging. Antibody-based PET tracers, like those targeting Nectin-4, CAIX, and uPAR, are under investigation for their diagnostic and theranostic potential, and initial studies indicate that these agents may offer advantages over conventional imaging and FDG PET. Conclusions: Molecular imaging is a rapidly evolving field in urothelial cancer, offering improved diagnostic and prognostic capabilities. While 18F FDG PET-CT has shown utility in staging, further prospective research is needed to establish and refine standardised protocols and validate new tracers. Advances in theranostics and precision imaging may revolutionise urothelial cancer management, enhancing the ability to tailor treatments and improve patient outcomes.

Naphtho[1,2-b][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.

The P2X4 receptor is implicated in various pathological conditions, including neuropathic pain and cancer. This study reports the development of 1,4-naphthodiazepinedione-based P2X4 receptor antagonists aimed at both therapeutic applications and potential use as PET tracers for imaging P2X4 receptor expression in cancer. Structure-activity relationship studies aided by docking studies and molecular dynamics simulations led to a series of compounds with potent P2X4 receptor antagonism, promising in vitro inhibition of interleukin-1β release in THP-1 cells and suitability for radiolabeling with fluorine-18. The most potent compounds were further evaluated for their physicochemical properties, metabolic stability, and in vivo biodistribution using PET imaging in mice. While these antagonists exhibited strong receptor binding and serum stability, rapid in vivo metabolism limited their potential as PET tracers, highlighting the need for further structural optimization. This study advances the understanding of P2X4 receptor antagonism and underscores the challenges in developing effective PET tracers for this target.

Preparation and preclinical evaluation of 68Ga-labeled alendronate analogs for diagnosis of bone metastases.

Bone is one of the most common target organs for distant metastases of solid tumors, which imposes a heavy burden on society. Early diagnosis of bone metastases is of great significance and positron emission tomography (PET) imaging plays an important role in the diagnosis of bone metastases. PET tracers applied for diagnosing bone metastases are constantly being updated, but they all have certain limitations like a relatively low bone/kidney ratio or no capacity to label therapeutic radionuclides. Alendronate, a representative bisphosphonate (BP), has been usually considered the standard clinical treatment for bone related diseases. In this study, alendronate was strategically modified with different linkers in an attempt to improve target/non-target ratios and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was used as the chelator. Finally, three 68Ga-labeled tracers were successfully developed. The results showed that [68Ga]Ga-AABP1/2/3 all exhibited high radiochemical purity, biosafety, and excellent stability. In the biodistribution study of normal BALB/c mice, [68Ga]Ga-AABP3, when modified with phenylalanine and β-alanine as the linker, showed the highest bone/non-bone ratio at 1.5 h. In micro-PET/CT imaging of normal BALB/c mice, [68Ga]Ga-AABP3 showed the highest SUVmax value at the bones (2.24 ± 0.16 at 1.5 h). In micro-PET/CT imaging of the mouse model of bone metastases, compared with [68Ga]Ga-AABP1 and [68Ga]Ga-AABP2, the SUVmax in the foci after injection of [68Ga]Ga-AABP3 was the highest (2.64 ± 0.08 at 0.5 h and 2.67 ± 0.10 at 1.5 h), significantly higher than that of the contralateral normal bone. Besides, [68Ga]Ga-AABP3 showed the highest tumor/non-tumor ratio at 1.5 h. The results suggest that [68Ga]Ga-AABP3 has the potential for diagnosis of bone metastases. Furthermore, AABP3 with the chelator DOTA could also be labeled with 177Lu or 225Ac, providing possibility for further application in radioligand therapy.

Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ

BackgroundPoly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [18F]FluorThanatrace and [18F]PARPi.Results[carbonyl-11C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [carbonyl-11C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection.ConclusionsAlthough [carbonyl-11C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated.

Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates.

mRNA delivered using lipid nanoparticles (LNPs) has become an important subunit vaccine modality, but mechanisms of action for mRNA vaccines remain incompletely understood. Here, we synthesized a metal chelator-lipid conjugate enabling positron emission tomography (PET) tracer labeling of LNP/mRNA vaccines for quantitative visualization of vaccine trafficking in live mice and non-human primates (NHPs). Following i.m. injection, we observed LNPs distributing through injected muscle tissue, simultaneous with rapid trafficking to draining lymph nodes (dLNs). Deltoid injection of LNPs mimicking human vaccine administration led to stochastic LNP delivery to 3 different sets of dLNs. LNP uptake in dLNs was confirmed by histology, and cellular analysis of tissues via flow cytometry identified antigen-presenting cells as the primary cell type responsible for early LNP uptake and mRNA translation. These results provide insights into the biodistribution of mRNA vaccines administered at clinically relevant doses, injection volumes, and injection sites in an important large animal model for vaccine development.

Utilisation of the Innovative [18F]-Labelled Radiotracer [18F]-BIBD-071 Within HR+ Breast Cancer Xenograft Mouse Models.

Background/Objectives: Aromatase plays a crucial role in the conversion of androgens to oestrogens and is often overexpressed in hormone-dependent tumours, particularly breast cancer. [18F]BIBD-071, which has excellent binding affinity for aromatase and good pharmacokinetics, has potential for the diagnosis and treatment of aromatase-related diseases. The MCF-7 cell line, which is hormone receptor-positive (HR+), was used in the assessment of the novel [18F]-labelled radiotracer [18F]BIBD-071 via positron emission tomography (PET) imaging of an HR+ breast cancer xenograft model. Methods: [18F]BIBD-071 was synthesised, radiolabelled, and then subjected to in vitro stability testing. MCF-7 cells were cultured and implanted into BALB/c nude mice to establish subcutaneous tumour models. MicroPET/CT imaging was conducted after injection of the tracer at 1 and 2 h, and a blocking study was also conducted using the aromatase inhibitor letrozole. A block experiment was used to prove the specificity of the probe. Biodistribution studies were performed at 0.5, 1, and 2 h post injection (p.i.). Immunofluorescence was used to assess aromatase expression in MCF-7 cells. Results: [18F]BIBD-071 showed excellent in vitro stability and specific uptake in an MCF-7 xenograft tumour model. MicroPET/CT imaging at 1 and 2 h p.i. revealed excellent tumour visualisation with a favourable tumour-to-background ratio. Biodistribution data revealed high tracer uptake in the liver, small intestine, and stomach, with significant washout from the bloodstream and tumour over time. The tumour uptakes at 0.5 h, 1 h, and 2 h were 3.84 ± 0.13, 2.5 ± 0.17, and 2.54 ± 0.32, respectively. The tumour uptake significantly decreased between 0.5 h and 1 h (p < 0.0001), whereas there was no significant difference between 1 and 2 h. The tumour/background ratios at 0.5 h, 1 h, and 2 h were 1.19 ± 0.03, 1.12 ± 0.17, and 1.42 ± 0.11, respectively. Immunofluorescence confirmed robust aromatase expression in MCF-7 cells, which was correlated with [18F]BIBD-071 tumour uptake. Conclusions: [18F]BIBD-071 is a promising PET tracer for diagnosing and monitoring HR+ breast cancer, warranting further research into hormone-dependent cancers.

Current Progress and Future Directions in Non-Alzheimer's Disease Tau PET Tracers.

Alzheimer's disease (AD) and non-AD tauopathies are dominant public health issues driven by several factors, especially in the aging population. The discovery of first-generation radiotracers, including [18F]FDDNP, [11C]PBB3, [18F]flortaucipir, and the [18F]THK series, for the in vivo detection of tauopathies has marked a significant breakthrough in the fields of neuroscience and radiopharmaceuticals, creating a robust new category of labeled compounds: tau positron emission tomography (PET) tracers. Subsequently, other tau PET tracers with improved binding properties have been developed using various chemical scaffolds to target the three-repeat/four-repeat (3R/4R) tau folds in AD. In 2020, [18F]flortaucipir was approved by the U.S. Food and Drug Administration for PET imaging of tau pathology in adult patients with cognitive deficits undergoing evaluation for AD. Despite remarkable progress in the development of AD tau PET tracers, imaging agents for rare non-AD tauopathies (4R tauopathies [predominantly expressing a 4R tau isoform], involved in progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and globular glial tauopathy, and 3R tauopathies [predominantly expressing a 3R tau isoform], such as Pick's disease) remain substantially underdeveloped. In this review, we discuss recent progress in tau PET tracer development, with particular emphasis on clinically validated tracers for AD and their potential use for non-AD tauopathies. Additionally, we highlight the critical need for further development of tau PET tracers specifically designed for non-AD tauopathies, an area that remains significantly underexplored despite its importance in advancing the understanding and diagnosis of these disorders.

Cysteine-Specific 18F and NIR Dual Labeling of Peptides via Vinyltetrazine Bioorthogonal Conjugation for Molecular Imaging.

Radiolabeled peptides are vital for positron emission tomography (PET) imaging, yet the 18F-labeling peptides remain challenging due to harsh conditions and time-consuming premodification requirements. Herein, we developed a novel vinyltetrazine-mediated bioorthogonal approach for highly efficient 18F-radiolabeling of a native peptide under mild conditions. This approach enabled radiosynthesis of various tumor-targeting PET tracers, including targeting the neurofibromin receptor (18F-P10a), the integrin αvβ3 (18F-P12a), and the platelet-derived growth factor receptor β (18F-ZPDGFRβ), with a radiochemical yield exceeding 90%. Preliminary evaluations revealed excellent hydrophilicity across these tracers, with 18F-P12a effectively visualizing integrin αvβ3 expression (tumor uptake: 1.57 ± 0.54%ID/g at 2 h). Additionally, we explored the potential for development of PET/near-infrared (NIR) dual-labeling agents using this method. The dual-modality agent 18F-Cy5-P12d enables specificity and colocalized imaging integrin αvβ3 expression (tumor uptake: 1.35 ± 0.24%ID/g at 2 h). Overall, this strategy offers a versatile platform for peptide radiolabeling and dual-modality agent development.

Identification of novel tau positron emission tomography tracers for chronic traumatic encephalopathy by comprehensive in silico screening and molecular dynamics simulation.

Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive mild traumatic brain injury, is characterized neuropathologically by abnormal hyperphosphorylated tau accumulation. Early detection of tau deposition in the brain is crucial for the prevention and evaluation of CTE. Positron emission tomography (PET) tracers can image specific proteins, while the optimal PET tracer for CTE tau fibrils remains unidentified. In this study, structure-based virtual screening and CNS PET MPO algorithms were utilized to identify candidates for novel tau PET tracers from 23 000 compounds in the ChemDiv CNS BBB library. A total of 8 μs molecular dynamics simulations were then employed to evaluate their binding affinity and atomic-level interaction with CTE tau protofibrils. The results indicate that V017-7820 (CNS-4), S776-0061 (CNS-12), S567-0465 (CNS-18), and T828-0465 (CNS-25) exhibit higher docking scores and binding free energies with CTE tau protofibrils while also satisfying the fundamental physicochemical properties of PET tracers. Further simulation analyses reveal that CNS-4 has the strongest binding affinity to tau protofibrils among the four compounds. Hydrophobic, π-π stacking, and hydrogen bonding interactions are the primary driving forces for the binding of these compounds to CTE tau protofibrils. In particular, CNS-12 and CNS-25 exhibit more intense hydrophobic and π-π stacking interactions, whereas CNS-4 and CNS-25 exhibit stronger hydrogen bonding interactions. This study identifies promising lead compounds for tau PET tracers and highlights their mechanism of binding to CTE tau protofibrils, which provides new insights for further screening and development of novel PET tracers for CTE diagnosis.

Reproducibility and repeatability of 18F-(2S, 4R)-4-fluoroglutamine PET imaging in preclinical oncology models.

Measurement of repeatability and reproducibility (R&R) is necessary to realize the full potential of positron emission tomography (PET). Several studies have evaluated the reproducibility of PET using 18F-FDG, the most common PET tracer used in oncology, but similar studies using other PET tracers are scarce. Even fewer assess agreement and R&R with statistical methods designed explicitly for the task. 18F-(2S, 4R)-4-fluoro-glutamine (18F-Gln) is a PET tracer designed for imaging glutamine uptake and metabolism. This study illustrates high reproducibility and repeatability with 18F-Gln for in vivo research. Twenty mice bearing colorectal cancer cell line xenografts were injected with ~9 MBq of 18F-Gln and imaged in an Inveon microPET. Three individuals analyzed the tumor uptake of 18F-Gln using the same set of images, the same image analysis software, and the same analysis method. Scans were randomly re-ordered for a second repeatability measurement 6 months later. Statistical analyses were performed using the methods of Bland and Altman (B&A), Gauge Reproducibility and Repeatability (Gauge R&R), and Lin's Concordance Correlation Coefficient. A comprehensive equivalency test, designed to reject a null hypothesis of non-equivalence, was also conducted. In a two-way random effects Gauge R&R model, variance among mice and their measurement variance were 0.5717 and 0.024. Reproducibility and repeatability accounted for 31% and 69% of the total measurement error, respectively. B&A repeatability coefficients for analysts 1, 2, and 3 were 0.16, 0.35, and 0.49. One-half B&A agreement limits between analysts 1 and 2, 1 and 3, and 2 and 3 were 0.27, 0.47, and 0.47, respectively. The mean square deviation and total deviation index were lowest for analysts 1 and 2, while coverage probabilities and coefficients of the individual agreement were highest. Finally, the definitive agreement inference hypothesis test for equivalency demonstrated that all three confidence intervals for the average difference of means from repeated measures lie within our a priori limits of equivalence (i.e. ± 0.5%ID/g). Our data indicate high individual analyst and laboratory-level reproducibility and repeatability. The assessment of R&R using the appropriate methods is critical and should be adopted by the broader imaging community.

Radiosynthesis and evaluation of novel 18F labeled PET ligands for imaging monoacylglycerol lipase.

Monoacylglycerol lipase (MAGL) is a 33kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC50=18.6nM and (S)-6, IC50=1.6nM). In vitro autoradiography studies of [18F](R)-6 (codenamed [18F]MAGL-2304) and [18F](S)-6 (codenamed [18F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [18F](S)-6. Dynamic PET imaging studies revealed that [18F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [18F](S)-6 uptake in the brain, suggesting that [18F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.