The potential utility of (2S,4R)-4-[18F] fluoroglutamine as a novel metabolic imaging marker for inflammation explored by rat models of arthritis and paw edema.

Purpose: (2S,4R)-4-[18F]fluoroglutamine ([18F]FGln) is a promising metabolic imaging marker in cancer. Based on the fact that major inflammatory cells are heavily dependent on glutamine metabolism like cancer cells, we explored the potential utility of [18F]FGln as a metabolic imaging marker for inflammation in two rat models: carrageenan-induced paw edema (CIPE) and collagen-induced arthritis (CIA). Procedures: The CIPE model (n = 4) was generated by injecting 200 µL of 3% carrageenan solution into the left hind paw three hours before the PET. The CIA model (n = 4) was generated by injecting 200 µg of collagen emulsion subcutaneously at the tail base 3-4 weeks before the PET. A qualitative scoring system was used to assess the severity of paw inflammation. After a CT scan, 15.7 ± 4.9 MBq of [18F]FGln was injected via the tail vein, followed by a dynamic micro-PET scan for 90 minutes under anesthesia with isoflurane. The standard uptake value of [18F]FGln was measured by placing a volume of interest in each paw. The non-injected right hind paws of the CIPE model rats served as controls for both models. The paws with CIA were pathologically examined after PET. Results: In CIPE models, uptake in the injected paw was higher compared to the non-injected paw by 52-83%. In CIA models, uptake in the paws with severe inflammation was higher than the averaged controls by 54-173%, while that with mild and no inflammation was slightly higher (33%) and lower (-7%), respectively. Combined overall, the [18F]FGln uptake in CIA showed a significant positive correlation with inflammation severity (r = 0.88, P = 0.009). The pathological findings confirmed profound inflammation in CIA. Conclusions: [18F]FGln uptake was increased in both acute and chronic inflammation, and the uptake level was significantly correlated with the severity, suggesting its potential utility as a novel metabolic imaging marker for inflammation.

Synthesis and Biological Evaluation of Fluorine-18 and Deuterium Labeled l-Fluoroalanines as Positron Emission Tomography Imaging Agents for Cancer Detection.

To fully explore the potential of 18F-labeled l-fluoroalanine for imaging cancer and other chronic diseases, a simple and mild radiosynthesis method has been established to produce optically pure l-3-[18F]fluoroalanine (l-[18F]FAla), using a serine-derivatized, five-membered-ring sulfamidate as the radiofluorination precursor. A deuterated analogue, l-3-[18F]fluoroalanine-d3 (l-[18F]FAla-d3), was also prepared to improve metabolic stability. Both l-[18F]FAla and l-[18F]FAla-d3 were rapidly taken up by 9L/lacZ, MIA PaCa-2, and U87MG cells and were shown to be substrates for the alanine-serine-cysteine (ASC) amino acid transporter. The ability of l-[18F]FAla, l-[18F]FAla-d3, and the d-enantiomer, d-[18F]FAla-d3, to image tumors was evaluated in U87MG tumor-bearing mice. Despite the significant bone uptake was observed for both l-[18F]FAla and l-[18F]FAla-d3, the latter had enhanced tumor uptake compared to l-[18F]FAla, and d-[18F]FAla-d3 was not specifically taken up by the tumors. The enhanced tumor uptake of l-[18F]FAla-d3 compared with its nondeuterated counterpart, l-[18F]FAla, warranted the further biological investigation of this radiotracer as a potential cancer imaging agent.

Granulomatous mastitis and pectoralis major muscle defect following polyacrylamide hydrogel injection: a case report and literature review.

Background: Breast augmentation through the injection of polyacrylamide hydrogel (PAAG) was a popular procedure in the past, but it has since been prohibited due to various complications, including masses, migration, infection, inflammation, and even cancer. However, there were rare cases of granulomatous mastitis with pectoralis major muscle defect following PAAG injection for breast augmentation. Case Description: A 40-year-old female patient presented with a swollen and suppurative mass in her left breast and was insensitive to antibiotics. She was admitted to our department for further treatment after 7 months with progressive local and general symptoms. Ultrasound imaging showed ill-defined heterogeneous echoes, and contrast-enhanced magnetic resonance imaging (MRI) revealed non-mass enhancement lesions in the multiregional distribution in Breast Imaging-Reporting and Data System 4A (BI-RADS 4A) with oedema in the retroglandular space and multiple enlarged lymph nodes in the ipsilateral axilla. Intraoperative observations revealed necrotic tissues, multiple abscesses, residual mucoid PAAG prosthesis diffused into the mammary glands and intramuscularly into the pectoralis muscle, and partial loss of pectoralis major muscle. Histopathological results revealed foreign-body granulomas accompanied by gel-like granular PAAG and proliferative inflammatory cells. She recovered after undergoing the characteristic surgical management in our center under general anesthesia and had no recurrence during the 2-year follow-up. Conclusions: This case revealed that PAAG injection for augmentation mammaplasty, even after the removal operation, could result in subsequent complications, including granulomatous mastitis and pectoralis major muscle damage. PAAG filler complications are difficult to treat, therefore, it is essential to establish appropriate and effective therapeutic procedures.

Prediction models for postoperative recurrence of non-lactating mastitis based on machine learning.

OBJECTIVES: This study aims to build a machine learning (ML) model to predict the recurrence probability for postoperative non-lactating mastitis (NLM) by Random Forest (RF) and XGBoost algorithms. It can provide the ability to identify the risk of NLM recurrence and guidance in clinical treatment plan. METHODS: This study was conducted on inpatients who were admitted to the Mammary Department of Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine between July 2019 to December 2021. Inpatient data follow-up has been completed until December 2022. Ten features were selected in this study to build the ML model: age, body mass index (BMI), number of abortions, presence of inverted nipples, extent of breast mass, white blood cell count (WBC), neutrophil to lymphocyte ratio (NLR), albumin-globulin ratio (AGR) and triglyceride (TG) and presence of intraoperative discharge. We used two ML approaches (RF and XGBoost) to build models and predict the NLM recurrence risk of female patients. Totally 258 patients were randomly divided into a training set and a test set according to a 75%-25% proportion. The model performance was evaluated based on Accuracy, Precision, Recall, F1-score and AUC. The Shapley Additive Explanations (SHAP) method was used to interpret the model. RESULTS: There were 48 (18.6%) NLM patients who experienced recurrence during the follow-up period. Ten features were selected in this study to build the ML model. For the RF model, BMI is the most important influence factor and for the XGBoost model is intraoperative discharge. The results of tenfold cross-validation suggest that both the RF model and the XGBoost model have good predictive performance, but the XGBoost model has a better performance than the RF model in our study. The trends of SHAP values of all features in our models are consistent with the trends of these features' clinical presentation. The inclusion of these ten features in the model is necessary to build practical prediction models for recurrence. CONCLUSIONS: The results of tenfold cross-validation and SHAP values suggest that the models have predictive ability. The trend of SHAP value provides auxiliary validation in our models and makes it have more clinical significance.

Staged operation in the surgical treatment of granulomatous lobular mastitis.

Background: Granulomatous lobular mastitis (GLM) is a chronic inflammatory breast condition characterized by an unclear etiology and an undefined therapeutic approach. Surgical intervention is considered an alternative modality for managing GLM. Staged operation is the predominant and characteristic surgical approach in the treatment of GLM in our center; therefore, we evaluated the efficacy of staged operative techniques in this cohort study. Methods: We retrospectively reviewed 212 patients with GLM who underwent staged operation between August 2020 and July 2022 in the inpatient department of our institute. Their clinical history information, clinic complaints, treatment details, surgical outcomes, follow-up results, and scores on the satisfaction questionnaire were analyzed. The patients were called for follow-up and consultation with a deadline of August 2023. Results: The median follow-up time was 27 months (range, 14-37 months). In total, 212 patients were treated with three different staged procedures according to the individual assessment and patient willingness, including 168 patients who underwent one-stage debridement operation and two-stage suture operation (DO + SO), 25 patients who underwent one-stage debridement operation without suture (DO), and 19 patients who underwent one-stage debridement and simultaneous suture operation (DSO). The median recovery time was 29 days (range, 14-60 days). A minority of patients developed postoperative complications, including effusion (1.89%), flap ischemia (0.94%), areola-nipple ischemia (0.94%) and sinus tract formation (2.36%). The scores of the satisfaction questionnaire were 43.10±3.09, and 186 patients (87.74%) gave high scores for postoperative breast appearance. Only 5 of 212 patients (2.36%) developed recurrence. Conclusions: Staged operation performed in our institute is an effective and safe surgical therapy in patients with GLM, yielding a short recovery time, low recurrence and good cosmetic results.

Adolescent Non-Puerperal Mastitis: Risk Factors, Clinical Characteristics, and Prognosis Analysis.

Purpose: To determine the risk factors, clinical characteristics, and prognosis of adolescent non-puerperal mastitis patients. Patients and methods: A retrospective analysis was conducted on 10 cases of NPM in adolescents who underwent surgical treatment at Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine from August 2021 to August 2023. We analyze the patient's general information, clinical characteristics, related medical history, laboratory indicators, breast magnetic resonance imaging examination, postoperative pathology, prognosis, etc. Results: The clinical manifestations of NPM in adolescents mainly included redness, swelling and pain in the breasts, congenital nipple retraction, and extensive lesion range. Inflammatory markers and prolactin were elevated. Magnetic resonance imaging showed circular enhancement with abscess formation as the main type. All patients underwent surgical treatment with a fast recovery time after surgery. No recurrence was observed during follow-up and the postoperative breast appearance was satisfactory. Multivariate Logistic regression analysis indicated that congenital nipple retraction, elevated prolactin levels and trauma were independent risk factors for adolescents non-puerperal mastitis. Conclusion: Adolescent non-puerperal mastitis is a rare and unique type. Summarizing its main risk factors, clinical characteristics, and prognosis provides a basis for further research.

LC/MS-based untargeted lipidomics reveals lipid signatures of nonpuerperal mastitis.

BACKGROUND: Nonpuerperal mastitis (NPM) is a disease that presents with redness, swelling, heat, and pain during nonlactation and can often be confused with breast cancer. The etiology of NPM remains elusive; however, emerging clinical evidence suggests a potential involvement of lipid metabolism. METHOD: Liquid chromatography‒mass spectrometry (LC/MS)-based untargeted lipidomics analysis combined with multivariate statistics was performed to investigate the NPM lipid change in breast tissue. Twenty patients with NPM and 10 controls were enrolled in this study. RESULTS: The results revealed significant differences in lipidomics profiles, and a total of 16 subclasses with 14,012 different lipids were identified in positive and negative ion modes. Among these lipids, triglycerides (TGs), phosphatidylethanolamines (PEs) and cardiolipins (CLs) were the top three lipid components between the NPM and control groups. Subsequently, a total of 35 lipids were subjected to screening as potential biomarkers, and the chosen lipid biomarkers exhibited enhanced discriminatory capability between the two groups. Furthermore, pathway analysis elucidated that the aforementioned alterations in lipids were primarily associated with the arachidonic acid metabolic pathway. The correlation between distinct lipid populations and clinical phenotypes was assessed through weighted gene coexpression network analysis (WGCNA). CONCLUSIONS: This study demonstrates that untargeted lipidomics assays conducted on breast tissue samples from patients with NPM exhibit noteworthy alterations in lipidomes. The findings of this study highlight the substantial involvement of arachidonic acid metabolism in lipid metabolism within the context of NPM. Consequently, this study offers valuable insights that can contribute to a more comprehensive comprehension of NPM in subsequent investigations. TRIAL REGISTRATION: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Number: 2019-702-57; Date: July 2019).

An improved synthesis of [18 F]VAT and its precursor.

The vesicular acetylcholine transporter (VAChT) in the brain is an important presynaptic cholinergic biomarker, and neuroimaging studies of VAChT may provide in vivo information about psychiatric and neurologic conditions including Alzheimer's disease that are not accessible by other methods. The 18 F-labeled radiotracer, ((-)-(1-(-8-(2-[18 F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone ([18 F]VAT, 1), was reported as a selective and high affinity ligand for the in vivo imaging of VAChT. The synthesis of [18 F]VAT has been reported in a two-step procedure with total 140 min, which includes preparation of 2-[18 F]fluoroethyltosylate and alkylation of benzovesamicol (-)-5 precursor with this radiosynthon using two different automated production modules consecutively. A multiple step synthetic route was employed for the synthesis of stereospecific precursor benzovesamicol (-)-5, which is difficult to be adapted for scale-up. To make the production of this tracer more amenable for clinical imaging, we present an improved total synthesis protocol to attain [18 F]VAT: (1) a tosylethoxy group being pre-installed tosylate precursor (-)-8 is synthesized to render a simple one-step radiofluorination under mild conditions; (2) The key optically active intermediate benzovesamicol (-)-5 was obtained via the regio- and enantio-enriched ring-opening amination of meso-epoxide 3 with 4-phenylpiperidine derivative 2 under catalysis of a chiral salenCo(III) catalyst 4b, which dramatically simplifies the synthetic route of the tosylate precursor (-)-8. [18 F]VAT 1 was prepared within ~65 min with desired chemical and radiochemical purities, via a fully automated procedure, using a commercial PET tracer production module. The final drug product was obtained as a sterile, pyrogen-free solution that conforms United States Pharmacopeia (USP) <823> requirements.

Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clinical diagnoses, we have developed a positron emission tomography (PET) radiotracer based on a selective BTK inhibitor, remibrutinib. [18F]PTBTK3 is an aromatic, 18F-labeled tracer that was synthesized in 3 steps with a 14.8 ± 2.4% decay-corrected radiochemical yield and ≥99% radiochemical purity. The cellular uptake of [18F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/severe combined immunodeficiency) mice, and the tumor uptake of [18F]PTBTK3 in BTK-positive JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-negative U87MG xenografts (0.41 ± 0.11% ID/cc). In the JeKo-1 xenografts, tumor uptake was blocked up to 62% by remibrutinib, indicating the BTK-dependent uptake of [18F]PTBTK3 in tumors.

Effectiveness of the Sanyin Formula Plus Chemotherapy on Survival in Women With Triple-Negative Breast Cancer: A Randomized Controlled Trial.

Purpose: To evaluate the efficacy of the Sanyin formula (SYF) plus conventional standard chemotherapy in operable triple-negative breast cancer (TNBC) patients, a randomized controlled trial was implemented at 5 hospitals and cancer centers in China between May 23, 2016, and October 31, 2019. Materials and Methods: Female patients aged 18 to 80 years with operable TNBC after definitive surgery were screened and enrolled. The exclusion criteria included metastatic disease, other tumors, or locally advanced disease. Patients were randomly divided into groups SYF plus conventional standard chemotherapy and placebo plus conventional standard chemotherapy at a ratio of 1:1. The primary endpoint of the investigation was disease-free survival (DFS), and secondary endpoints included overall survival (OS) and toxicity. Results: A total of 252 operable female TNBC patients were randomized to receive SYF plus conventional standard chemotherapy (N = 127) or a placebo plus conventional standard chemotherapy (N = 125). At a median follow-up of 51 months, 5-year DFS time was longer in those assigned to SYF plus conventional standard chemotherapy compared with placebo plus conventional standard chemotherapy (94.2%vs 85.5%, hazard ratio [HR] = 0.40; 95%CI, 0.17-0.97; P = 0.034). The absolute benefit for 5-year DFS was 8.7% in the SYF plus conventional standard chemotherapy group. No statistically significant difference was observed in OS between the two groups (P = 0.23). Patients with negative node status benefited more from SYF plus conventional standard chemotherapy treatment (HR = 0.21, P-interaction = 0.013) in accordance with the exploratory subgroup analyses of DFS. Conclusions: The results of the present study suggest that the traditional Chinese medicine SYF plus conventional chemotherapy regimens is an effective alternative adjuvant chemotherapy strategy for female operable TNBC patients. Clinical Trial Registration: https://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR-IPR-16008590.

Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography.

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones.

A Multi-Ligand Imaging Study Exploring GABAergic Receptor Expression and Inflammation in Multiple Sclerosis.

PURPOSE: The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABAA binding and the innate immune response is explored using positron emission tomography (PET) with [11C] flumazenil (FMZ) and [11C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages. PROCEDURES: Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABAA receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function. A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest. RESULTS: GABAA receptor binding was higher throughout the cortex in MS patients (5.72 ± 0.91) as compared with HC (4.70 ± 0.41) (p = 0.002). A significant correlation was found between FMZ binding and PK-PET within the cortex (r = 0.61, p < 0.001) and among the occipital (r = 0.61, p = 0.012), parietal (r = 0.49, p = 0.041), and cingulate (r = 0.32, p = 0.006) regions. CONCLUSIONS: A higher GABAA receptor density in MS subjects compared with HC was observed and correlated with innate immune activity. Our observations demonstrate that immune-driven GABAergic abnormalities may be present in MS.

A general 11C-labeling approach enabled by fluoride-mediated desilylation of organosilanes.

Carbon-11 (11C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce 11C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS) 11C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [11C]CO2 and [11C]CH3I into molecules with diversified structures. It provides facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology.

Synthesis of [1-11C]Butanol via a facile solid phase extraction protocol.

A facile synthesis method for the preparation of [1-11C]butanol, a regional cerebral blood flow imaging agent, was developed. Using a solid phase extraction method, the highly polar and volatile molecule [1-11C]butanol was quickly concentrated, purified, and released as final product; boasting high radiochemical and chemical purities as well as high radiochemical yields. The final drug product was obtained as a sterile, pyrogen-free solution that conforms United States Pharmacopeia (USP) <823> requirements.

Associations Between Delivery Mode and Early Childhood Body Mass Index Z-Score Trajectories: A Retrospective Analysis of 2,685 Children From Mothers Aged 18 to 35 Years at Delivery.

Objective: To investigate the association between cesarean delivery (CD) and trajectory patterns of age- and sex-specific body mass index (BMI) z-score in early childhood. Methods: A retrospective cohort study was conducted among 2,685 children whose maternal age at the time of birth was between 18 and 35 years, and birth data and anthropometric measurement data during their ages 3-60 months were collected. A group-based trajectory modeling approach was used to identify distinct BMI z-score trajectories, and multinomial logistic regressions were applied to estimate the associations among CD (both elective and non-elective combined), elective and non-selective CD, and BMI z-score trajectory classes. Results: Of the 2,685 participants, 46.5% (N = 1,248) were born by vaginal delivery (VD), 20.7% (N = 556) by elective CD, and 32.8% (N = 881) by non-elective CD. Five BMI z-score trajectory patterns were identified, and they were "increasing from moderate to high" (10.1%, n = 270), "increasing from mild to moderate" (34.2%, n = 919), "increasing from low to high" (10.5%, n = 283), "stable mild" (30.1%, n = 808), and "stable low" (15.1%, n = 405) groups. Compared with children delivered by VD, those who delivered by CD (both elective and non-elective combined), elective CD, and non-elective CD were associated with the "increasing from moderate to high" trajectory [odds ratio (OR) = 1.61, 95% confidence interval (CI): 1.13-2.29; OR = 1.64, 95%CI: 1.06-2.54; and OR = 1.59, 95%CI: 1.05-2.39, respectively] and were also associated with the "increasing from low to high" trajectory (OR = 1.60, 95%CI: 1.17-2.19, OR = 1.75, 95%CI: 1.16-2.63; and OR = 1.53, 95%CI: 1.00-2.34, respectively). Conclusion: Both elective and non-elective CD were associated with the risk of accelerated weight gain in early childhood.

Glutathione S-transferase M1 and T1 polymorphisms, and their interactions with smoking on risk of low birth weight: a meta-analysis.

Background: Published data regarding the association between glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) gene polymorphisms and risk of low birth weight (LBW) remains inconclusive, and data on the interactions between the two gene polymorphisms and smoking for LBW susceptibility is lacking. To clarify these associations, a meta-analysis was conducted.Methods: A comprehensive literature search was conducted in multiple databases until 11 January 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed or random effects model.Results: Thirty-eight studies from 17 articles concerning maternal and neonatal GSTM1 and GSTT1 gene polymorphism with LBW risk were included in this meta-analysis, and nine studies from five articles provided data of maternal tobacco exposure status during pregnancy. Maternal GSTM1 null genotype was associated with increased LBW risk (OR = 1.27, 95% CI: 1.12-1.45). There was a nonsignificant but positive association (OR = 1.19, 95% CI: 0.97-1.46) between the maternal GSTT1 null genotype and the LBW risk in the overall analysis. There was a null association between neonatal GSTM1 or GSTT1 polymorphism and LBW risk. There were significant associations between the maternal GSTM1 null and GSTT1 null genotype and LBW risk (for the former, OR = 3.85, 95% CI: 1.68-8.81; for the later, OR = 1.88, 95% CI: 1.01-3.50) in individuals with active smoking, respectively.Conclusion: Maternal GSTM1 and GSTT1 null genotypes, but not neonatal genotypes, are suggested to increase LBW susceptibility, and there are interactions between active smoking and these polymorphisms in the development of LBW.

Synthesis of l-[4-11 C]Asparagine by Ring-Opening Nucleophilic 11 C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor.

The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains a challenge. This is especially true for the synthesis of carbon-11-labeled AAs given the short half-life of carbon-11 (11 C, t1/2 =20.4 min). A facile synthetic pathway to prepare enantiomerically pure 11 C-labeled l-asparagine was developed using a partially protected serine as a starting material with a four-step transformation providing a chiral five-membered cyclic sulfamidate as the radiolabeling precursor. Its structure and absolute configuration were confirmed by X-ray crystallography. Utilizing a [11 C]cyanide nucleophilic ring opening reaction followed by selective acidic hydrolysis and deprotection, enantiomerically pure l-[4-11 C]asparagine was synthesized. Further optimization of reaction parameters, including base, metal ion source, solvent, acid component, reaction temperature and reaction time, a reliable two-step method for synthesizing l-[4-11 C]asparagine was presented: within a 45±3 min (n=5, from end-of-bombardment), the desired enantiomerically pure product was synthesized with the initial nucleophilic cyanation yield of 69±4 % (n=5) and overall two-step radiochemical yield of 53±2 % (n=5) based on starting [11 C]HCN, and with radiochemical purity of 96±2 % (n=5).

Dynamic Precision Phenotyping Reveals Mechanism of Crop Tolerance to Root Herbivory.

The western corn rootworm (WCR; Diabrotica virgifera virgifera LeConte) is a major pest of maize (Zea mays) that is well adapted to most crop management strategies. Breeding for tolerance is a promising alternative to combat WCR but is currently constrained by a lack of physiological understanding and phenotyping tools. We developed dynamic precision phenotyping approaches using 11C with positron emission tomography, root autoradiography, and radiometabolite flux analysis to understand maize tolerance to WCR Our results reveal that WCR attack induces specific patterns of lateral root growth that are associated with a shift in auxin biosynthesis from indole-3-pyruvic acid to indole-3-acetonitrile. WCR attack also increases transport of newly synthesized amino acids to the roots, including the accumulation of Gln. Finally, the regrowth zones of WCR-attacked roots show an increase in Gln turnover, which strongly correlates with the induction of indole-3-acetonitrile-dependent auxin biosynthesis. In summary, our findings identify local changes in the auxin biosynthesis flux network as a promising marker for induced WCR tolerance.

An efficient and practical synthesis of [2-(11)C]indole via superfast nucleophilic [(11)C]cyanation and RANEY® Nickel catalyzed reductive cyclization.

A rapid method for the synthesis of carbon-11 radiolabeled indole was developed using a sub-nanomolar quantity of no-carrier-added [(11)C]cyanide as radio-precursor. Based upon a reported synthesis of 2-(2-nitrophenyl)acetonitrile (), a highly reactive substrate 2-nitrobenzyl bromide () was evaluated for nucleophilic [(11)C]cyanation. Additionally, related reaction conditions were explored with the goal of obtaining of highly reactive 2-(2-nitrophenyl)-[1-(11)C]acetonitrile () while inhibiting its rapid conversion to 2,3-bis(2-nitrophenyl)-[1-(11)C]propanenitrile (). Next, a RANEY® Nickel catalyzed reductive cyclization method was utilized for synthesizing the desired [2-(11)C]indole with hydrazinium monoformate as the active reducing agent. Extensive and iterative screening of basicity, temperature and stoichiometry was required to overcome the large stoichiometry bias that favored 2-nitrobenzylbromide () over [(11)C]cyanide, which both caused further alkylation of the desired nitrile and poisoned the RANEY® Nickel catalyst. The result is an efficient two-step, streamlined method to reliably synthesize [2-(11)C]indole with an entire radiochemical yield of 21 ± 2.2% (n = 5, ranging from 18-24%). The radiochemical purity of the final product was >98% and specific activity was 176 ± 24.8 GBq µmol(-1) (n = 5, ranging from 141-204 GBq µmol(-1)). The total radiosynthesis time including product purification by semi-preparative HPLC was 50-55 min from end of cyclotron bombardment.

Total cyanide mass measurement with micro-ion selective electrode for determination of specific activity of carbon-11 cyanide.

In this research, we aim to directly measure the specific activity (SA) of the carbon-11 cyanide ([(11)C]CN¯) produced by our in-house built automated [(11)C]HCN production system and to identify the major sources of (12)C-cyanide ((12)CN¯). The [(11)C]CN¯ is produced from [(11)C]CO2, which is generated by the (14)N(p,α)(11)C nuclear reaction using a cyclotron. Direct measurement of cyanide concentrations was accomplished using a relatively inexpensive, and easy to use ion selective electrode (ISE) which offered an appropriate range of sensitivity for detecting mass. Multiple components of the [(11)C]HCN production system were isolated in order to determine their relative contributions to (12)CN¯ mass. It was determined that the system gases were responsible for approximately 30% of the mass, and that the molecular sieve/nickel furnace unit contributed approximately 70% of the mass. Beam on target (33µA for 1 and 10min) did not contribute significantly to the mass. Additionally, we compared the SA of our [(11)C]HCN precursor determined using the ISE to the SA of our current [(11)C]CN¯ derived radiotracers determined by HPLC to assure there was no significant difference between the two methods. These results are the first reported use of an ion selective electrode to determine the SA of no-carrier-added cyanide ion, and clearly show that it is a valuable, inexpensive and readily available tool suitable for this purpose.