Radiosynthesis and Evaluation of [11C]HD-800, a High Affinity Brain Penetrant PET Tracer for Imaging Microtubules.

Microtubules (MTs) are highly abundant throughout the cytoskeleton, and their dysfunction is implicated in the pathogenesis of malignancies, various neurodegenerative disorders, and brain injuries. Validated radiotracers reported so far for MTs are [11C]paclitaxel, [18F]fluoropaclitaxel, and [11C]docetaxel; however, they are well-characterized substrates of efflux transporters and consequently have poor uptake into the brain due to minimal blood brain barrier (BBB) penetration. PET imaging of MT expression requires radiolabeled BBB penetrating MT ligands, and it may offer a direct and more sensitive approach for early diagnosis, monitoring disease progression, and treatment effects in brain diseases and assessing the clinical potential of targeted therapeutics and treatments. We have identified N-(4-methoxyphenyl)-N-5-dimethylfuro[2,3-d]pyrimidin-4-amine (HD-800) as a high affinity and selective colchicine site tubuline inhibitor amenable to radiolabel with C-11, a positron emitting isotope. HD-800 and desmethyl-HD-800 were synthesized in one step with 75% and 80% yields respectively from commercial synthons. The radiosynthesis of [11C]HD-800 was achieved in 45 ± 5% yield at EOS. Ex vivo biodistribution binding data of [11C]HD-800 indicate that the radioligand penetrated the BBB and it was retained in brain with 75% specific binding. Apart from the brain, specific binding was observed in muscle (55%), heart (50%), lungs (43%), blood (37%), and pancreas (30%). MicroPET imaging in mice showed excellent binding in brain that was blocked by preadministration of unlabeled HD-800 and a colchicine site binding MT ligand MPC-6827. The above results indicate that [11C]HD-800 may be a suitable PET ligand for the in vivo quantification of MT inside and outside the brain.

Radiosynthesis and in Vivo Evaluation of [11C]MPC-6827, the First Brain Penetrant Microtubule PET Ligand.

Abnormalities of microtubules (MTs) are implicated in the pathogenesis of many CNS diseases. Despite the potential of an MT imaging agents, no PET ligand is currently available for in vivo imaging of MTs in the brain. We radiolabeled [11C]MPC-6827, a high affinity MTA, and demonstrated its specific binding in rat and mice brain using PET imaging. Our experiments show that [11C]MPC-6827 has specific binding to MT in brain, and it is the first MT-binding PET ligand.

Comparison of Levosimendan versus Dobutamine in Patients with Moderate to Severe Left Ventricular Dysfunction Undergoing Off-pump Coronary Artery Bypass Grafting: A Randomized Prospective Study.

CONTEXT: Recent upsurge in referral of patients with compromised left ventricular (LV) function for cardiac surgery has led to an increasing use inotropes to achieve improvement of tissue perfusion in the perioperative period. AIMS AND OBJECTIVES: To compare the hemodynamic effects and immediate postoperative outcomes with levosimendan and dobutamine in patients with moderate to severe LV dysfunction undergoing off-pump coronary artery bypass grafting (OPCAB). SETTINGS AND DESIGN: University teaching hospital, randomized control study. MATERIALS AND METHODS: Eighty patients were randomly divided into two groups of 40 each. Group I received levosimendan at 0.1 µg/kg/min and Group II received dobutamine at 5 µg/kg/min. Hemodynamic data were noted at 30 min, during obtuse marginal grafting, 1, 6, 12, and 24 h after surgery. Heart rate (HR), mean arterial pressure (MAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI), left ventricular stroke work index (LVSWI) and right ventricular stroke work index (RVSWI), mixed venous oximetry (SvO2), and lactate were measured. STATISTICAL ANALYSIS USED: Chi-square and Student's t-test. RESULTS: The HR, MAP, PCWP, SVRI, and PVRI were lower in Group I when compared to Group II. Group I patients showed a statistically significant increase in LVSWI, RVSWI, and CI, when compared to Group II. Comparatively, Group I patients maintained higher SvO2and lower lactate levels. Duration of ventilation, Intensive Care Unit (ICU), and hospital stay were lower in Group I. CONCLUSIONS: Levosimendan was associated with statistically significant increase in indices of contractility (CI, LVSWI, and RVSWI) and decrease in PCWP during and after OPCAB. Levosimendan group had lower incidence of atrial fibrillation, shorter length of ICU, and hospital stay.

Delayed diagnosis of traumatic diaphragmatic rupture with herniation of the liver: a case report.

Diaphragmatic rupture is a potentially life-threatening clinical situation. It occurs as a result of high-velocity blunt or penetrating injury to the abdomen and thorax. Acute traumatic rupture of the diaphragm may go undetected, and there is often a delay between the injury and diagnosis. Right-sided rupture is less common due to hepatic protection and increased strength of the right hemidiaphragm. We report the case of a 28-year-old man who was admitted with breathlessness to our hospital, 72 hours after trauma. Since clinical signs and symptoms were nonspecific, helical computed tomography was done, which revealed diaphragmatic rupture with hepatothorax. Emergency thoracotomy was done to repair diaphragmatic rent. The postoperative period was uneventful, and the patient was discharged three weeks later.