Preclinical and evaluation of [C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates.

This paper describes the preclinical validation of the radioligand [C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (αR) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central αR. autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [H]ORM-13070.

The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).

A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

The synthesis and in vivo evaluation of [18F]PF-9811: a novel PET ligand for imaging brain fatty acid amide hydrolase (FAAH).

Introduction: Fatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development. Companion molecular imaging probes are needed, however, to assess FAAH inhibition in the nervous system in vivo.

Harderian gland adenectomy: a method to eliminate confounding radio-opacity in the assessment of rat brain metabolism by 18F-fluoro-2-deoxy-D-glucose positron emission tomography.

The 18F isotope of fluoro-2-deoxy-D-glucose (FDG) is a radiotracer commonly used in positron emission tomography (PET) for determining regional metabolic activity in the brain. However, in rats and many other species with nictitating membranes, harderian glands located just behind the eyes aggressively incorporate 18F-FDG to the extent that PET images of the brain become obscured. This radioactive spillover, or 'partial volume error,' combined with the limited spatial resolution of microPET scanners (1.

Reproducibility of common semi-quantitative parameters for evaluating lung cancer glucose metabolism with positron emission tomography using 2-deoxy-2-[18F]fluoro-D-glucose.

Purpose: Positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been used for various cancers, but reproducibility of common utilized semi-quantitative parameters, such as the maximal single pixel standardized uptake value (SUV) and effective glycolytic volume (EGV), remains unknown. Knowledge of precision is essential for applying these parameters to treatment monitoring. The purpose of this investigation was to assess the precision of PET results obtained by repeated examinations of patients with untreated lung cancer.

Comparison of attenuation-corrected and non-corrected FDG-PET images for axillary nodal staging in newly diagnosed breast cancer.

Purpose: The aim of this work is to compare the accuracy of non-attenuation-corrected (NAC) and attenuation-corrected (AC) PET images using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) in assessment of the axilla in patients with newly-diagnosed, untreated, primary breast cancers, and to determine the frequency of extra-axillary findings.

Patients And Methods: FDG-PET was performed in 36 patients with breast cancer one hour following the intravenous injection of approximately 370 MBq of FDG. Patients were imaged prior to axillary dissection to prospectively confirm the presence or absence of axillary metastases.

Diabetes Decreases FDG Accumulation in Primary Lung Cancer.

OBJECTIVE: To compare kinetics and accumulation of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in primary lung cancer between diabetic and non-diabetic patients using positron emission tomography (PET).METHODS: Five diabetic patients and 21 non-diabetic patients underwent dynamic FDG-PET to image untreated primary lung cancers. Standardized uptake value normalized for lean body mass (SUL) was determined in tumor, blood, muscle, and lung.

FDG-PET Determination of Metabolically Active Tumor Volume and Comparison with CT.

PURPOSE: To determine if tumor volume, in addition to tumor metabolic activity, can be assessed noninvasively from attenuation-corrected fluorodeoxyglucose (FDG)-PET imaging using a semiautomated method.METHODS: CT and FDG-PET scanning was performed in 14 patients, eight with newly diagnosed untreated malignancies, and six patients with progressive non-Hodgkin's lymphoma (NHL). Tumor volume was determined from CT scans by summation of manually drawn regions of interest over tumor.

A positron-emitting internal marker for identification of normal tissue by positron emission tomography: phantom studies and validation in patients.

Purpose: This study evaluated in a phantom model and verified in patients with lung cancer whether the use of an internal positron-emitting labeled marker could localize a critical structure by positron emission tomography (PET) imaging and verify multimodality image registration.

Materials And Methods: An initial device and method were developed to demonstrate by dedicated PET the location of the normal esophagus in a phantom and in three patients using a column of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) solution between proximal and distal gas phases in polyurethane tubing. The device was assessed for possible loss of radioactivity.

Update on hybrid conjugate-view SPECT tumor dosimetry and response in 131I-tositumomab therapy of previously untreated lymphoma patients.

Unlabelled: A study of the use of (131)I-labeled tositumomab, preceded by an unlabeled tositumomab predose, for therapy of 76 previously untreated non-Hodgkin's lymphoma patients has been completed at the University of Michigan. Fifty-two of the 76 treated patients were imaged once during therapy with SPECT to assist in dosimetric estimation. In this article, the patient's average tumor dose, estimated by a hybrid method using that SPECT, is compared with the same statistic estimated by pretherapy conjugate views.

FDG metabolism and uptake versus blood flow in women with untreated primary breast cancers.

The aim of this study was to determine the relationship between tumor blood flow and glucose utilization in women with untreated primary breast carcinomas. Noninvasive determinations of blood flow and glucose utilization with positron emission tomography (PET) were performed in 101 regions of tumor from nine women with untreated primary breast carcinoma. [(15)O]H(2)O PET scans of tumor blood flow were compared with fluorine-18 fluoro-2-deoxy- D-glucose (FDG) PET scans of tumor glucose metabolism.

Expression of hexokinase II and Glut-1 in untreated human breast cancer.

Expressions of HKII and Glut-1 were studied in untreated primary human breast cancers by immunohistochemistry. 79% of the breast cancers were HKII-positive and 61% were Glut-1-positive. Average positive malignant cell areas were 66 +/- 41% for HKII and 29 +/- 36% for Glut-1.

Volume reduction versus radiation dose for tumors in previously untreated lymphoma patients who received iodine-131 tositumomab therapy. Conjugate views compared with a hybrid method.

Background: A Phase II study of previously untreated patients with malignant low grade follicular lymphoma given a combination of unlabeled tositumomab and tositumomab labeled with iodine-131 has recently been completed. The responses of these patients have been characterized, and for some of them tumor dosimetry during therapy has been estimated not only by pretherapy tracer conjugate views but also by a hybrid method.

Methods: Available patients were studied if they had had a pelvic or abdominal tumor evaluation by single photon emission computed tomography (SPECT) and achieved a partial response.