Hidden in Plain Sight: Deciphering Chest Pain, Hypertension, and Elevated Creatinine to Unveil Aortic Dissection.

Chest pain is a common yet complex presentation in the emergency department, often requiring the exclusion of life-threatening conditions such as aortic dissection. Stanford type B aortic dissection, which affects the descending aorta, poses significant diagnostic and therapeutic challenges but can often be managed medically without immediate surgery. This case underscores the necessity of having a vigilant mindset, performing a detailed clinical examination, and including aortic dissection in the differential diagnosis, especially when typical symptoms are observed. The challenging part of this case was the investigation, as computed tomography angiography couldn't be performed, necessitating the use of magnetic resonance imaging for diagnosis. It highlights the importance of individualized patient care, vigilant monitoring, and comprehensive management strategies in the treatment of aortic dissection.

Occupational Lung Disease Causing Allergic Bronchopulmonary Aspergillosis: A Case Report.

Aspergillus fumigatus can induce allergic bronchopulmonary aspergillosis (ABPA), an immunological hypersensitivity reaction that frequently exacerbates the symptoms of cystic fibrosis and asthma patients. Due to persistent symptoms, a considerable percentage of patients with ABPA in India, a country where tuberculosis is widespread, are initially misdiagnosed as having pulmonary tuberculosis. We present a case of ABPA in a male industry worker, who was diagnosed after one year of having symptoms and has successfully recovered since.

Correlation of Mean Platelet Volume and Red Cell Distribution Width With HbA1c and Its Association With Microvascular Complications in Type 2 Diabetes Mellitus: A Cross-Sectional Study at a Tertiary Hospital in India.

INTRODUCTION: Diabetes mellitus type 2 (T2DM) is a metabolic disorder, and its prevalence is rising worldwide. The objective of the study was to investigate the association between mean platelet volume (MPV) and red cell distribution width (RDW) and the glycemic control marker HbA1c. So MPV and RDW could be used as prognostic indicators of deterioration of gluco-regulation in diabetes mellitus type 2 and the associated microvascular complications. METHODOLOGY: A cross-sectional study was conducted on 216 type 2 diabetic patients, who were divided into two groups based on HbA1c values (<7% and >7%). Red blood cell distribution width, mean platelet volume, plasma glucose estimation, fasting lipid profile, spot urine albumin creatinine ratio (ACR), direct ophthalmoscopic examination, and nerve conduction study were tested in all the patients. RESULTS: Of the 216 individuals diagnosed with type 2 diabetes mellitus, 210 exhibited inadequate glycemic control, establishing a statistically significant correlation with triglyceride levels, mean platelet volume, and blood sugar levels. The study revealed a significant association between MPV and RDW and HbA1c levels. Additionally, microvascular complications such as retinopathy, proteinuria, and neuropathy exhibited strong correlations in this patient cohort, emphasizing the interconnectedness of glycemic control and various health indicators in individuals with T2DM. CONCLUSION: This study provides significant results that mean platelet volume and red cell distribution can be used as markers in the diagnosis of microvascular complications in type 2 diabetes mellitus.

Serum Magnesium Levels and QTc Interval Prolongation As Prognostic Markers in Acute Myocardial Infarction: A Randomized Controlled Study.

Introduction Acute myocardial infarction (AMI) is frequently preceded by arrhythmias, which continue to be a prominent cause of abrupt fatality in AMI. Abnormal magnesium levels have been linked to the emergence of arrhythmia because it enhances myocardial metabolism and cardiac output and prevents calcium buildup and myocardial cell death by lowering arrhythmias. The objectives of this study were to evaluate serum magnesium levels and QTc interval as prognostic indicators in AMI patients during the initial 48 hours of hospital stay and to correlate these parameters with the Global Registry of Acute Coronary Events (GRACE) scoring. We studied AMI patients by dividing them into two groups: those with abnormal and those with normal serum magnesium levels. Methods After obtaining ethical approvals, patients were subjected to detailed history, which included sociodemographic details, drug history, clinical examination, and investigations such as creatine kinase myocardial band (CK-MB), CK-total, troponin-T, ECG (QTc interval), two-dimensional echocardiogram (2D-ECHO), serum creatinine and magnesium levels, heart rate, and blood pressure. We also calculated the GRACE score for all patients. Results We found that patients in the age group of 51-60 years were more prone to developing arrhythmias, and while AMI was more prevalent in males, the occurrence of arrhythmias was slightly higher in females with AMI. Anterior wall motion abnormality (AWMA) was the most predominant abnormality, and 12.3% of AWMA patients had arrhythmias. QTc interval was significantly longer in patients who developed arrhythmias. Interestingly, among patients with QTc prolongation, 35% patients had abnormal magnesium levels, while 65% had normal magnesium levels. In our study, of the 25 patients with hypermagnesemia, nine (36%) developed arrhythmias, while of the 75 patients with hypomagnesemia, 15 (20%) patients developed arrhythmias. Interestingly, we found that there was a positive correlation between GRACE score and serum magnesium as well as QTc interval prolongation. Lastly, among the six deaths reported, three (50%) patients had arrhythmias. Conclusion Overall, we conclude that serum magnesium levels play a pivotal role as a prognostic tool for arrhythmias and are a useful investigation during the initial 48 hours of admission in AMI patients.

The Relationship Between Fibrinogen and Glycated Hemoglobin (HbA1c) in Diabetic Foot Ulcers.

INTRODUCTION:  Diabetic foot ulcers (DFUs) are a common complication of diabetes that affects patients' quality and prognosis of life. The study aims to assess the correlation between fibrinogen and glycated hemoglobin (HbA1c) in DFUs at the first and sixth months and to compare fibrinogen levels with Wagner classification in DFU patients. METHODS:  This observational study was conducted at SRM Medical College Hospital and Research Centre from January 2021 to July 2022. Fifty diabetes patients with DFUs were selected, and informed consent was obtained before the study started. Blood samples were collected from all the participants for HbA1C, serum fibrinogen, hemoglobin, and white blood cells. In this study, data were entered into MS Excel (Microsoft Corporation, Redmond, WA) and analyzed using SPSS version 24 (IBM Corp., Armonk, NY). ANOVA and Pearson's correlation were used to examine the relationships between serum fibrinogen levels and clinical parameters. RESULTS:  Among 50 patients, the females were 16 (32%), and the males were 34 (68%). Most patients (34%) were in the 56-60 age group. Twenty patients had diabetes for 10 years, and 24 were diabetic for 11-15 years. The ankle-brachial index (ABI score) was mild in 14 patients (28%), moderate in 28 patients (56%), and normal in eight patients (16%). There is a significant difference in comparison between the Wagner classification and ABI. A significant difference was observed in fibrinogen at the first and sixth months between HbA1c first, third, and sixth months. Significant differences were also observed in fibrinogen and ABI in the first and sixth months. CONCLUSION:  Key findings include significant differences between fibrinogen and HbA1c levels (p < 0.0001) and a strong association between fibrinogen levels and ABI scores (p < 0.0001), underscoring fibrinogen's potential as an early marker for glycemic control and peripheral arterial disease in DFU patients. We concluded that simple fibrinogen estimation helps predict glycemic control in diabetic patients with DFUs.

Unveiling the Veiled: Enteroviral Meningitis Mimicking Idiopathic Intracranial Hypertension.

Meningitis is a significant health concern globally, with enterovirus (EV) being the most common cause of viral meningitis in adults. We discuss the case of a 57-year-old female patient with enteroviral meningitis manifesting as pseudotumor cerebri, posing significant clinical challenges. She presented with symptoms, signs, and radiological evidence suggesting idiopathic intracranial hypertension. The CSF analysis showed pleocytosis, which led to further investigations that unveiled a positive case of EV by real-time reverse transcription polymerase chain reaction analysis. This case highlights the fact that not all cases of raised intracranial pressure are detrimental or recalcitrant. It accentuates the need for thorough diagnostic evaluation and emphasizes the potential for favorable outcomes with conservative management.

Patterns of Cerebrovascular Accidents in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease that primarily affects young adults. It is characterized by the development of antiphospholipid antibodies (APL) and a wide range of macro- and microvascular symptoms. The primary causes of morbidity and mortality in APS are cardiovascular events. Subclinical atherosclerosis and cardiovascular events are associated with high-risk APL profiles, particularly with the presence of lupus anticoagulant and triple APL positivity (all three APL subtypes), co-existence with systemic lupus erythematosus (SLE), and traditional risk factors like smoking, hypertension, obesity, and hyperlipemia. We present a case series involving three female stroke patients with APS. This series highlights the importance of immunological profiles in all stroke patients.

Study of electrocardiographic corrected QT interval and QT dispersion abnormalities, erythrocyte sedimentation rate, serum uric acid in patients with systemic lupus erythematosus.

INTRODUCTION: Systemic Lupus Erythematosus (SLE) is an autoimmune disease having a variety of clinical symptoms because of multiple organs being affected at once or progressively over time. Cardiovascular system (CVS) involvement is the third most frequent cause of death in SLE, among other factors. The prognosis can be determined by looking at QT interval measurements, which have shown an elevated risk of mortality from cardiovascular causes. METHODS: A case-control study was conducted on 80 patients (40 SLE patients and 40 controls) for a duration of 16 months. SLE patients and controls were identified from the general medicine and rheumatology outpatient department (OPD) based on the inclusion criteria. A thorough clinical examination was performed after obtaining a detailed clinical history. Baseline blood tests were then performed on the SLE patients and ECG was taken from both cases and controls. The serum uric acid level was measured using an automated analyzer, and the ESR was computed using Westergren's Method. The corrected QT interval (QTc) was estimated using Bazett's method. All the collected data were compared and analyzed using IBM SPSS Statistics version 23.0. RESULTS: The majority of age distribution among SLE patients and controls was 21-25 years (37.5%) (Mean - 15.7 ± 14.9 years). Duration of SLE was predominantly reported between 1 and 12 months (62.5%). Very high (40%) and high (40%) lupus disease activity was recorded in the majority as per the SELENA-SLEDAI score. There was a significant difference between QTc values among SLE patients and controls (t- 8.117) (p-.0005). Upon correlating SLEDAI with the QTc, QTd, ESR, and Uric acid parameters among the SLE patients, ESR parameters were found to be moderately correlated (r-0.460) with the SLEDAI which was statistically significant (p- .003). CONCLUSION: QTc interval and ESR values can be a simple and potential method for early detection of cardiac involvement in SLE patients with active disease activity. This will not only facilitate early diagnosis of disease activity, but it will also provide an affordable and accessible avenue for low and middle-income countries to decrease the SLE burden.

Adropin: A crucial regulator of cardiovascular health and metabolic balance.

Adropin, a peptide discovered in 2008, has gained recognition as a key regulator of cardiovascular health and metabolic balance. Initially identified for its roles in energy balance, lipid metabolism, and glucose regulation, adropin has also been found to improve cardiovascular health by enhancing endothelial function, modulating lipid profiles, and reducing oxidative stress. These protective mechanisms suggest that adropin may be able to help prevent conditions such as atherosclerosis, hypertension, and other cardiovascular diseases. Research has established connections between adropin and cardiovascular risk factors, such as obesity, insulin resistance, and dyslipidemia, positioning it as a valuable biomarker for evaluating cardiovascular disease risk. New studies highlight adropin's diagnostic and prognostic significance, showing that higher levels are linked to better cardiovascular outcomes, while lower levels are associated with a higher risk of cardiovascular diseases. This review aims to summarize current knowledge on adropin, emphasizing its significance as a promising focus in the intersection of cardiovascular health and metabolic health. By summarizing the latest research findings, this review aims to offer insights into the potential applications of adropin in both clinical practice and research, leading to a deeper understanding of its role in maintaining cardiovascular and metabolic health.

Neutrophil lymphocyte ratio and heart type fatty acid binding protein as a prognostic marker in Myocardial infarction within 48 h of admission.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is a measure of systemic inflammation, whereas Heart type fatty acid protein (HFABP) is a cytosolic protein released early after acute coronary syndrome (ACS). The aim of this research study is to determine whether NLR and H-FAB are useful in predicting the prognosis in patients with ST segment elevation myocardial infarction (STEMI) 48 h after admission. This is a prospective observational study conducted on 97 patients who had been admitted to emergency room with ST-elevation myocardial infarction in their ECG in a tertiary care centre of south India. The neutrophil-lymphocyte ratio was measured at the time of admission, 24th hour and 48th hour, and then compared with the outcome. To determine their significance in the MI episode, troponin-I and H-FABP were also measured. RESULTS: A significant correlation was found in the final outcomes of patients and the NLR at the time of admission and at 48 h (p = 0.01). Additionally, a substantial correlation between NLR and various degrees of LV dysfunction was also observed (p = 0.01). H-FABP was found to be positive in all 97 of the patients examined, whereas Troponin-I was only found to be positive in 56.7%. CONCLUSION: The study's findings, indicated strong correlations between NLR and LVEF, indicated that NLR might serve as an early predictor of cardiac events which could be either poor prognosis or higher mortality. This research found that H-FABP may serve as an early MI diagnostic marker.

Platelet indices as prognostic markers of ischemic stroke and their correlation with lipid profile.

OBJECTIVE: Stroke is the cause of one in eight deaths and adds a dreadful burden of disability for the patients. Ischemic stroke is caused by a loss of blood supply to brain due to sudden occlusion of the arterial system, caused by an emboli or thrombus. Our aim was to correlate platelet indices, total cholesterol ratio, and various comorbidities with stroke. METHODS: A cross-sectional study was performed from 2020-2022 with 132 stroke patients admitted to the SRM Medical College Hospital and Research Center, India. Detailed clinical examination was performed. Venous blood samples were drawn at the time of admission to estimate platelet count, mean platelet volume (MPV), platelet distribution width (PDW), and platelet crit (PCT). Overnight fasting serum samples were obtained for lipid profiling. RESULTS: Among the participants in our study, maximum belonged to the age group 50 to 59 years (34.1%) and majority were males (79.5%). In terms of comorbidities, 85.6% of the participants had diabetes, 42.4% had hypertension and 22% had dyslipaedemia. All platelet and lipid parameters were found to be similar between patients with and without comorbidities. While all platelet indices increased with the increase in severity of stroke, we found that PDW is most reliable in predicting stroke with an area under the receiver operator curve of 0.942, with a sensitivity and specificity of 92.1% at cut-off value 14. All platelet parameters also significantly increased in patients with severe lipid dysfuction, establishing a correlation between lipid profile, platelet indices and stroke. CONCULSION: We found a significant relationship between all platelet parameters and stroke. Thus, we believe that patients with risk factors for atherosclerosis should have their platelet indices assessed periodically before the development of cerebrovascular events. Furthermore, dyslipidemia if properly treated, is a modifiable risk factor for stroke, which can decrease morbidity and mortality leading to a healthier society.

Radiosynthesis and evaluation of [11C]AG-488, a dual anti-angiogenetic and anti-tubulin PET ligand.

Combinations of antiangiogenic and cytotoxic agents show promising results in the treatment of cancer. However, there is a lack of single agent with both antiangiogenic and cytotoxic activities for clinical application. AG-488 aka FLAG-003 is a novel ligand with established antiangiogenetic properties via activation of receptor thymidine kinase (RTK) and anti-tubulin properties in tumor cells. AG-488 is also reported to reduce tumor volume and prolong survival in preclinical animal models of glioblastoma multiforme, breast cancer and is in clinical stage. Higher expression of RTKs and tubulins is reported in various cancers. This study reveals the development of [11C]AG-488, a high affinity dual target inhibitor binding to RTK and anti-tubulin activities. We rationale that antiangiogenic RTK and anti-tubulin activity of [11C]AG-488 may enhance the tumor to tissue ratio, assisting in cancer drug development. [11C]AG-488 was synthesized in 35 ± 5 % radiochemical yield by radiomethylating the corresponding phenolate using [11C]CH3I. MicroPET studies in mice indicated blood-brain barrier penetration of [11C]AG-488 and retention in the brain. However, blocking studies with antitubulin and RTK agent HD-800 and microtubule depolymerizing agent MPC-6827 show increased binding of [11C]AG-488 in brain. The pattern of tracer binding in blocking conditions is similar to the baseline conditions. The higher binding may be due to the increased plasma uptake of radiotracer or the formation of more free tubulins due to microtubule dynamic instability during the blocking conditions.

Preclinical evaluation of a microtubule PET ligand [11C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models.

BACKGROUND: Microtubules are abundant in brain and their malfunctioning occurs in the early-to-advanced stages of neurodegenerative disorders. At present, there is no in vivo test available for a definitive diagnosis of most of the neurodegenerative disorders. Herein, we present the microPET imaging of microtubules using our recently reported Positron Emission Tomography (PET) tracer, [11C]MPC-6827, in transgenic mice models of tau pathology (rTg4510) and amyotrophic lateral sclerosis pathology (SOD1*G93A) and compared to corresponding age-matched controls. METHODS: Automated synthesis of [11C]MPC-6827 was achieved in a GE-FX2MeI/FX2M radiochemistry module. In vivo PET imaging studies of [11C]MPC-6827 (3.7 ± 0.8 MBq) were performed in rTg4510 and SOD1*G93A mice groups and their corresponding littermates (n = 5 per group). Dynamic PET images were acquired using a microPET Inveon system (Siemens, Germany) at 55 min for rTg4510 and 30 min for SOD1*G93A and corresponding controls. PET images were reconstructed using the 3D-OSEM algorithm and analyzed using VivoQuant version 4 (Invicro, MA). Tracer uptake in ROIs that included whole brain was measured as %ID/g over time to generate standardized uptake values (SUV) and time-activity curves (TACs). RESULTS: [11C]MPC-6827 exhibit a trend of lower tracer binding in mouse models of Alzheimer's disease (tau pathology, line rTg4510) and Amyotrophic Lateral Sclerosis (line SOD1*G93A) compared to wild-type littermates. CONCLUSIONS: Our finding indicates a trend of loss of microtubule binding of [11C]MPC-6827 in the whole brain of AD and ALS transgenic mice models compared to control mice. The pilot studies described herein show that [11C]MPC-6827 could be used as a PET ligand for preclinical and human brain imaging of Alzheimer's disease, ALS, and other neurodegenerative diseases. Preclinical Evaluation of a Microtubule PET Ligand [11C]MPC-6827 in Tau and Amyotrophic Lateral Sclerosis Animal Models. J. S. Dileep Kumar, Andrei Molotkov, Jongho Kim, Patrick Carberry, Sidney Idumonyi, John Castrillon, Karen Duff, Neil A. Shneider, Akiva Mintz.

In vivo evaluation of a microtubule PET ligand, [11C]MPC-6827, in mice following chronic alcohol consumption.

BACKGROUND: Excessive alcohol consumption is a global health burden and requires a better understanding of its neurobiology. A lower density of brain microtubules is found in alcohol-related human brain disease postmortem and in rodent models of chronic alcohol consumption. Here, we report in vivo imaging studies of microtubules in brain using our recently reported Positron Emission Tomography (PET) tracer, [11C]MPC-6827, in chronic alcohol-consuming adult male C57BL/6 J mice and control mice. METHODS: In vivo PET imaging studies of [11C]MPC-6827 (3.7 ± 0.8 MBq) were performed in two groups of adult male mice: (1) water-consuming control mice (n = 4) and (2) mice that consumed 20% alcohol (w/v) for 4 months using the intermittent 2-bottle choice procedure that has been shown to lead to signs of alcohol dependence. Dynamic 63 min PET images were acquired using a microPET Inveon system (Siemens, Germany). PET images were reconstructed using the 3D-OSEM algorithm and analyzed using VivoQuant version 4 (Invicro, MA). Tracer uptake in ROIs that included whole brain, prefrontal cortex (PFC), liver and heart was measured and plotted as %ID/g over time (0-63 min) to generate time-activity curves (TACs). RESULTS: In general, a trend for lower binding of [11C]MPC-6827 in the whole brain and PFC of mice in the chronic alcohol group was found compared with control group. No group difference in radiotracer binding was found in the peripheral organs such as liver and heart. CONCLUSIONS: This pilot study indicates a trend of loss of microtubule binding in whole brain and prefrontal cortex of chronic alcohol administered mice brain compared to control mice, but no loss in heart or liver. These results indicate the potential of [11C]MPC-6827 as a PET ligand for further in vivo imaging investigations of AUD in human.

Antibacterial and anticancer potential of Brassica oleracea var acephala using biosynthesised copper nanoparticles.

INTRODUCTION: Brassica oleracea var acephala was studied for preliminary phytochemical screening. The results showed that the ethanolic crude extract of the leaf contain high phytochemical activity hence B.oleracea var acephala is rich in flavonoids, phenolic compounds, carbohydrates and phytosterols. MATERIALS AND METHODS: The ethanolic extract was used to synthesise copper nanoparticles. The copper nanoparticles were successfully synthesised from copper sulphate solution which was identified by the colour change from dark green colour of the extract. Thus the B.oleracea var acephala is a good source to synthesis copper nanoparticles. The synthesised copper nanoparticles were characterised using Scanning Electron Microscope (SEM) analysis. The SEM image displayed the high-density nanoparticles synthesised by leaf extracts and that the nanoparticles were crystals in shape. RESULTS: The copper nanoparticles (CNP) bind to the leaf extract. B.oleracea var acephala also has shown the antimicrobial and antioxidant activity. A comparative study was done between ethanolic its crude extract and nanoparticles. Both extracts exhibited zone of inhibition and better antioxidant potential but the CuNPs shows major zone of inhibition and showed more antioxidant activity. Anticancer activity of B.oleracea var acephala against Cervical HeLa cell line was confirmed using ethanolic crude extract and CNP. The results showed that HeLa cells proliferation was inhibited with increasing concentration of ethanolic crude extract and copper nanoparticles. From the results, it was seen that percentage viability of the cancer cells decreased with increased concentration of the samples whereas cytotoxicity against HeLa cell lines increased with the increased concentration of the samples. CONCLUSION: Thus B.oleracea var acephala possesses anticancer activity against HeLa cell lines.

A new distribution record of Albunea groeningi (Crustacea: Anomura: Decapoda: Albuneidae) from the Digha Coast, West Bengal, India.

Members of the genus Albunea Weber, 1795 (family Albuneidae) are commonly known as sand crabs. Albuneidae contains 59 species belonging to 13 genera (Boyko McLaughlin 2010; WoRMS 2019), of which four genera and nine species are known only as fossils. Most species are relatively uncommon and adapted to living in sandy habitats (Boyko Harvey 1999). Among the 24 species of Albunea, four are known only as fossils (WoRMS 2019). The diversity and distributions of most albuneids were reported by Boyko (2002, 2010).

Radiosynthesis and evaluation of [18F]FMTP, a COX-2 PET ligand.

BACKGROUND: The upregulation of cyclooxygenase-2 (COX-2) is involved in neuroinflammation associated with many neurological diseases as well as cancers of the brain. Outside the brain, inflammation and COX-2 induction contribute to the pathogenesis of pain, arthritis, acute allograft rejection, and in response to infections, tumors, autoimmune disorders, and injuries. Herein, we report the radiochemical synthesis and evaluation of [18F]6-fluoro-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)pyrimidin-4-amine ([18F]FMTP), a high-affinity COX-2 inhibitor, by cell uptake and PET imaging studies. METHODS: The radiochemical synthesis of [18F]FMTP was optimized using chlorine to fluorine displacement method, by reacting [18F]fluoride/K222/K2CO3 with the precursor molecule. Cellular uptake studies of [18F]FMTP was performed in COX-2 positive BxPC3 and COX-2 negative PANC-1 cell lines with unlabeled FMTP as well as celecoxib to define specific binding agents. Dynamic microPET image acquisitionwas performed in anesthetized nude mice (n = 3), lipopolysaccharide (LPS) induced neuroinflammation mice (n = 4), and phosphate-buffered saline (PBS) administered control mice (n = 4) using a Trifoil microPET/CT for a scan period of 60 min. RESULTS: A twofold higher binding of [18F]FMTP was found in COX-2 positive BxPC3 cells compared with COX-2 negative PANC-1 cells. The radioligand did not show specific binding to COX-2 negative PANC-1 cells. MicroPET imaging in wild-type mice indicated blood-brain barrier (BBB) penetration and fast washout of [18F]FMTP in the brain, likely due to the low constitutive COX-2 expression in the normal brain. In contrast, a ~ twofold higher uptake of the radioligand was found in LPS-induced mice brain than PBS treated control mice. CONCLUSIONS: Specific binding to COX-2 in BxPC3 cell lines, BBB permeability, and increased brain uptake in neuroinflammation mice qualifies [18F]FMTP as a potential PET tracer for studying inflammation.

Synthesis, in vitro and in vivo evaluation of 11C-O-methylated arylpiperazines as potential serotonin 1A (5-HT1A) receptor antagonist radiotracers.

BACKGROUND: Serotonin 1A (5-HT1A) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-11C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT1A receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers. RESULTS: Syntheses of 1-3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT1A receptors. Binding of 1-3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α1-adrenergic receptors (4-6-fold less potent than that for 5-HT1A receptor). Radioligands [11C]1-3 were efficiently prepared by 11C-O-methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7-11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [11C]1 and [11C]2. In contrast, significant brain uptake of [11C]3 was observed with an early peak SUV of 4-5. However, [11C]3 displayed significant off-target binding attributed to α1-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies. CONCLUSION: Despite efficient radiolabeling, results from PET imaging experiments limit the application of [11C]3 for in vivo quantification of 5-HT1A receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT 1A receptors or α1-adrenergic receptors.

In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands.

Altered dynamics of microtubules (MT) are implicated in the pathophysiology of a number of brain diseases. Therefore, radiolabeled MT targeted ligands that can penetrate the blood brain barrier (BBB) may offer a direct and sensitive approach for diagnosis, and assessing the clinical potential of MT targeted therapeutics using PET imaging. We recently reported two BBB penetrating radioligands, [11C]MPC-6827 and [11C]HD-800 as specific PET ligands for imaging MTs in brain. The major metabolic pathway of the above molecules is anticipated to be via the initial labeling site, O-methyl, compared to the N-methyl group. Herein, we report the radiosynthesis of N-11CH3-MPC-6827 and N-11CH3-HD-800 and a comparison of their in vivo binding with the corresponding O-11CH3 analogues using microPET imaging and biodistribution methods. Both O-11CH3 and N-11CH3 labeled MT tracers exhibit high specific binding and brain. The N-11CH3 labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-11CH3 labeled tracers, [11C]MPC-6827 and [11C]HD-800 respectively.

Radiosynthesis and evaluation of [11C]CMP, a high affinity GSK3 ligand.

Dysfunction of GSK3 is implicated in the etiology of many brain, inflammatory, cardiac diseases, and cancer. PET imaging would enable in vivo detection and quantification of GSK3 and can impact the choice of therapy, allow non-invasive monitoring of disease progression and treatment effects. In this report, the synthesis and evaluation of a high affinity GSK3 ligand, [11C]2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide, ([11C]CMP, (3), (IC50 = 3.4 nM, LogP = 1.1) is described. [11C]CMP was synthesized in 25 ±â€¯5% yield by radiomethylating the corresponding phenolate using [11C]CH3I. The radioligand exhibited modest uptake in U251 human glioblastoma cell lines with ∼50% specific binding. MicroPET studies in rats indicated negligible blood-brain barrier (BBB) penetration of [11C]CMP, despite its high affinity and suitable logP value for BBB penetration. However, administration of cyclosporine prior to [11C]CMP injection showed significant improvement in brain radioactivity uptake and the tracer binding. This finding indicates that [11C]CMP might be a P-gp efflux substrate and therefore has some limitations for routine in vivo PET evaluations in brain.