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Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.

Ergothioneine (ERGO) is a rare amino acid mostly found in fungi, including mushrooms, with recognized antioxidant activity to protect tissues from damage by reactive oxygen species (ROS) components. Prior to this publication, the biodistribution of ERGO has been performed solely in vitro using extracted tissues. The aim of this study was to develop a feasible chemistry for the synthesis of an ERGO PET radioligand, [ 11 C]ERGO, to facilitate in vivo study. The radioligand probe was synthesized with identical structure to ERGO by employing an orthogonal protection/deprotection approach. [ 11 C]methylation of the precursor was performed via [ 11 C]CH 3 OTf to provide [ 11 C]ERGO radioligand. The [ 11 C]ERGO was isolated by RP-HPLC with a molar activity of 690 TBq/mmol. To demonstrate the biodistribution of the radioligand, we administered approximately 37 MBq/0.1 mL in 5XFAD mice, a mouse model of Alzheimer’s disease via the tail vein. The distribution of ERGO in the brain was monitored using 90-min dynamic PET scans. The delivery and specific retention of [ 11 C]ERGO in an LPS-mediated neuroinflammation mouse model was also demonstrated. For the pharmacokinetic study, the concentration of the compound in the serum started to decrease 10 min after injection while starting to distribute in other peripheral tissues. In particular, a significant amount of the compound was found in the eyes and small intestine. The radioligand was also distributed in several regions of the brain of 5XFAD mice, and the signal remained strong 30 min post-injection. This is the first time the biodistribution of this antioxidant and rare amino acid has been demonstrated in a preclinical mouse model in a highly sensitive and non-invasive manner.

Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer’s disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this work, we report the design and synthesis of a novel [11C]promethazine PET radioligand for future in vivo studies. The [11C]promethazine was isolated by RP-HPLC with radiochemical purity >95% and molar activity of 48 TBq/mmol. The specificity of the probe was demonstrated using human hippocampal tissues via autoradiography.

BackgroundRadiopharmaceuticals capable of targeting the fibroblast activation protein have become widely utilized in the research realm as well as show great promise to be commercialized; with [68Ga]Ga-FAPI-46 being one of the most widely utilized. Until now the synthesis has relied on generator-produced gallium-68. Here we present a developed method to utilize liquid-target cyclotron-produced gallium-68 to prepare [68Ga]Ga-FAPI-46.ResultsA fully-automated manufacturing process for [68Ga]Ga-FAPI-46 was developed starting with the 68Zn[p,n]68Ga cyclotron bombardment to provide [68Ga]GaCl3, automated purification of the [68Ga]GaCl3, chelation with the precursor, and final formulation/purification. The activity levels produced were sufficient for multiple clinical research doses, and the final product met all release criteria. Furthermore, the process consistently provides < 2% of Ga-66 and Ga-67 at the 4-h expiry, meeting the Ph. Eur. standards.ConclusionsThe automated radiosynthesis on the GE FASTlab 2 module purifies the cyclotron output into [68Ga]GaCl3, performs the labeling, formulates the product, and sterilizes the product while transferring to the final vial. Production of > 40 mCi (> 1480 MBq) of [68Ga]Ga-FAPI-46 in excellent radiochemical yield was achieved with all batches meeting release criteria.

The clinical translation of molecularly targeted therapeutics and imaging agents represents a cornerstone of precision oncology, with the global theranostics market projected to exceed $25 billion by 2030. However, the development of theragnostic agents or diagnostic companions remains constrained by analytical bottlenecks in quality control, such as target-binding fraction, which are increasingly required by regulatory agencies as product release criteria during the translation process. Current methods, including enzyme-linked immunosorbent assay (ELISA), which require specialized resources or external CROs, or bead-based assays for radiolabeled compounds, which involve complex multi-step protocols; these limitations and others hamper their practical implementation in clinical manufacturing environments. Assay delays can postpone clinical trial initiation, increase development costs, and delay patient access to these agents. We have developed and validated a rapid, size-exclusion high-performance liquid chromatography (SE-HPLC) method for the determination of target-binding fractions of labeled biologics. The method separates the unbound biologic from the larger antigen-bound complex, allowing for rapid quantification. We validated the method using a panel of fluorescently labeled antibodies (panitumumab-IRDye800CW, nivolumab-IRDye800CW) and radiolabeled biologics ([18F]GEH200521, [18F]NOTA-ABY-030), assessing linearity, specificity, and concentration independence. The SE-HPLC method achieved excellent separation of bound and unbound species with a resolution (Rs) of 3.2. A strong linear relationship (R  = 0.999) was observed between the antigen-to-antibody ratio and the measured binding fraction. The method demonstrated high specificity, with no binding detected with non-target antigens. The total assay and analysis time was less than 35 min, a significant improvement over traditional methods. SE-HPLC provides a rapid, specific, and cost-effective alternative to traditional binding fraction assessment methods, reducing quality control timelines from weeks/hours to minutes. The method's compatibility with both fluorescent and radiolabeled biologics and integration with existing HPLC infrastructure represents a significant advancement in development workflows.

Purpose Upregulation of sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) lesions is associated with neuroinflammatory response. This study investigated the correlation between neuroinflammation and S1PR1 expression in the spinal cord of an experimental autoimmune encephalomyelitis (EAE) rat model of MS, using the S1PR1 positron emission tomography (PET) radiotracer [ 11 C]TZ3321. Procedures MicroPET imaging studies of [ 11 C]TZ3321 were performed to measure uptake of [ 11 C]TZ3321 in the spinal cord of EAE rats. Immunohistochemical staining was performed to confirm the overexpression of S1PR1 and other inflammatory biomarkers. Results MicroPET imaging demonstrated a 20–30 % increase in [ 11 C]TZ3321 uptake in the lumbar spinal cord of EAE rats versus sham controls at 35–60 min post injection. The increased uptake of [ 11 C]TZ3321 was correlated with the overexpression of S1PR1 in the lumbar spinal cord of EAE rats that was confirmed by immunohistochemical staining. Upregulated S1PR1 expression was associated with glial cell activation and immune cell infiltration. Conclusions MicroPET imaging modality with a specific radioligand [ 11 C]TZ3321 is able to assess the expression of S1PR1 in EAE rat lumbar spinal cord. This may provide a new approach to the assessment of neuroinflammatory response in MS and other inflammatory diseases.

Adults with Down syndrome (DS) are at increased risk for Alzheimer's disease (AD) due to APP triplication. Cholinergic system degeneration underlies many AD-related cognitive deficits, but cholinergic integrity in adults with DS is not well defined. We use [ F]-fluoroethoxybenzovesamicol ([ F]-FEOBV) PET imaging to measure regional cholinergic terminal density in adults with DS compared to age- and amyloid-matched neurotypical controls. Sixteen non-demented adults with DS were recruited from the Trial Ready Cohort - Down Syndrome and de novo to a cholinergic study (8 female, 35.5 years). Twenty (10 female, 35.5 years) age-matched and fifteen (15 female, 61.5 years) amyloid-matched participants were recruited for cognitively normal control groups. All subjects received [ F]-FEOBV PET and MRI scans, fifteen adults with DS and amyloid-matched individuals received amyloid scans ([ C]-PiB or [ F]-Florbetabir). Following normalization to MNI-space and partial volume correction, a voxelwise t-test compared [ F]-FEOBV uptake between adults with DS and age-matched controls. General linear models assessed the relationship between [ F]-FEOBV uptake, age, or amyloid in adults with DS. Group x age and group x amyloid interaction analyses assessed if [ F]-FEOBV relationships differed between adults with DS and control participants. Adults with DS exhibited increased [ F]-FEOBV uptake in the cerebellum, brainstem, thalamus, and cortical regions compared to age-matched neurotypical controls (p < 0.001). They also exhibited lower uptake in cortical clusters among older participants, along with a significant age x group interaction revealing a greater reduction in adults with DS compared to controls (p < 0.005). Additionally, adults with DS displayed lower [ F]-FEOBV uptake related to higher amyloid accumulation, showing a more significant decline compared to amyloid-matched controls (p < 0.005). All analyses had a minimum cluster size of 50. These data indicate an upregulation of cholinergic terminal markers in adults with DS by early adulthood, suggesting greater subsequent declines due to age and amyloid pathology relative to controls. Significant age and amyloid associations overlap in some regions, with more clusters exhibiting significant age-associated effects. This result suggests that declining regional [ F]-FEOBV uptake in adults with DS is influenced by both Alzheimer's-related pathology and aging, each playing distinct yet overlapping roles.

BACKGROUND Adults with Down syndrome (DS) have increased risk of Alzheimer's disease (AD). The cholinergic system declines in AD, underlying many cognitive deficits. We investigated the relationship between amyloid accumulation and cholinergic terminal density in adults with DS compared to amyloid‐matched controls. METHODS A total of 15 non‐demented adults with DS and 15 amyloid‐matched healthy controls were assessed for [18F]‐FEOBV uptake differences and [18F]‐FEOBV uptake relationships with amyloid accumulation and cognitive performance. RESULTS Adults with DS displayed greater [18F]‐FEOBV uptake than controls, with a similar uptake pattern. Amyloid‐associated differences in [18F]‐FEOBV uptake were observed in adults with DS. [18F]‐FEOBV uptake in adults with DS was positively associated with cognition. DISCUSSION Adults with DS display higher [18F]‐FEOBV uptake than amyloid‐matched controls but relatively lower [18F]‐FEOBV uptake in individuals with elevated amyloid. Thus, the cholinergic system appears to be adversely affected by AD pathology in individuals with DS, which may be relevant to cognitive decline. Highlights Adults with DS display greater cholinergic terminal density in specific ROIs than amyloid‐match controls. Adults with DS exhibit a similar pattern of cholinergic terminal density across the brain. The first association of cholinergic terminal density with AD pathology in non‐demented adults with DS. Adults with DS display a greater cholinergic terminal decline in association with amyloid accumulation than neurotypically developed age‐matched controls. Region‐specific cholinergic terminal density associated with cognitive performance in adults with DS.

Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in vascular smooth muscle cells from intimal lesions. PET imaging using S1PR1 as a biomarker would increase our understanding of its role in vascular pathologies including in-stent restenosis. The S1PR1 compound TZ3321 was synthesized for in vitro characterization and labeled with Carbon-11 for in vivo studies. The biodistribution of [11C]TZ3321 was evaluated in normal mice; microPET and immunohistochemistry (IHC) studies were performed using a murine femoral artery wire-injury model of restenosis. The high potency of TZ3321 for S1PR1 (IC50 = 2.13 ± 1.63 nM), and high selectivity (>1000 nM) for S1PR1 over S1PR2 and S1PR3 were confirmed. Biodistribution data revealed prolonged retention of [11C]TZ3321 in S1PR1-enriched tissues. MicroPET imaging of [11C]TZ3321 showed higher uptake in the wire-injured arteries of ApoE−/− mice than in injured arteries of wild-type mice (SUV 0.40 ± 0.06 vs 0.28 ± 0.04, n = 6, P < .001); FDG-PET showed no difference (SUV 0.98 ± 0.04 vs 0.94 ± 0.01, n = 6, P > .05). Post-PET autoradiography showed >4-fold higher [11C]TZ3321 retention in the injured artery of ApoE−/− mice than in wild-type mice. Subsequent IHC staining confirmed higher expression of S1PR1 in the neointima of the injured artery of ApoE−/− mice than in wild-type mice. This preliminary study supports the potential use of PET for quantification of the S1PR1 expression as a biomarker of neointimal hyperplasia.

Surgical management of head and neck squamous cell carcinoma (HNSCC) patients often requires resection of the deep cervical lymph nodes. Fluorescence guided surgery (FGS) is a growing area of oncologic surgery that has shown promise for this purpose, however, it is limited by the signal penetration through the neck. To address this, we sought to evaluate the efficacy of the anti-EGFR antibody [ In]panitumumab to detect metastatic lymph nodes both on preoperative imaging and intraoperatively. We hypothesized that the addition of a radiolabeled antibody would be safe and effective in detecting malignant tissue when given alone or together with the optical agent panitumumab-IRDye800CW (pan800). Seventeen patients were enrolled and received 5 mCi of [ In]panitumumab with nine patients (53%) receiving [ In]panitumumab and pan800. SPECT/CT scans were performed prior to surgical resection. Intraoperatively, patients underwent gamma tracing and the patients who received pan800 also underwent optical fluorescence imaging. Resected specimens were compared to final histopathology to determine the sensitivity and specificity of the two tracers. No adverse events related to the [ In]panitumumab were reported. SPECT/CT performed 3 days post-injection showed higher tumor-to-blood pool ratio compared to earlier scans (p = 0.04), and when compared to pathological assessment, could detect disease greater than 1 cm in diameter. Intraoperatively, resection of the primary tumor resulted in a significant drop in gamma counts (p < 0.001). detection of metastatic lymph nodes using the radiotracer was inconsistent and attributed to high background counts as patients who underwent surgery before 48 hours post-injection had significantly higher precordial counts than patients who underwent surgery after 48 hours, even when corrected for time, weight, and dose (p = 0.04). , metastatic lymph nodes had gamma counts almost twice that of benign (p < 0.0001). The separately dosed pan800 and [ In]panitumumab showed strong co-localization within metastatic lymph nodes (R = 0.87). Intravenous infusion of [ In]panitumumab in HNSCC patients is safe, whether administered alone or with pan800. Consistent with other studies, application of the radiotracer differentiated tumor containing tissue from benign. However, intraoperative use of the radiotracer to detect metastatic lymph nodes was limited by background signal at early timepoints and signal decay at later timepoints.