Structure-activity relationships of N-substituted 4-(trifluoromethoxy)benzamidines with affinity for GluN2B-containing NMDA receptors.

GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.

(11) C-labeled and (18) F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain.

The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping and eating disorders, neurodegeneration, neuroinflammation, mood disorders, and pruritus.

Radiation dose of the P-glycoprotein tracer 11C-laniquidar.

Unlabelled: Resistance to current drug therapy is an important issue in the treatment of epilepsy. Inadequate access of central nervous system drugs to their targets in the brain may be caused by overexpression or overactivity of multidrug transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier. Laniquidar, an inhibitor of P-gp, has been labeled with (11)C for use in PET studies of P-gp expression in humans.

Longitudinal amyloid imaging using 11C-PiB: methodologic considerations.

Unlabelled: Several methods are in use for analyzing (11)C-Pittsburgh compound-B ((11)C-PiB) data. The objective of this study was to identify the method of choice for measuring longitudinal changes in specific (11)C-PiB binding.

Methods: Dynamic 90-min (11)C-PiB baseline and follow-up scans (interval, 30 ± 5 mo) were obtained for 7 Alzheimer disease (AD) patients, 11 patients with mild cognitive impairment (MCI), and 11 healthy controls.

[11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: impact of epilepsy and drug-responsiveness.

Introduction: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar.

Methods: Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders".

Pharmacokinetic analysis of [18F]FAZA in non-small cell lung cancer patients.

Purpose: [(18)F]Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within a tumour. The aims of this study were to determine the optimal kinetic model along with validation of using alternatives to arterial blood sampling for analysing [(18)F]FAZA studies and to assess the validity of simplified analytical methods.

Methods: Dynamic 70-min [(18)F]FAZA PET/CT scans were obtained from nine non-small cell lung cancer patients.

Toward prediction of efficacy of chemotherapy: a proof of concept study in lung cancer patients using [¹¹C]docetaxel and positron emission tomography.

Purpose: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([(11)C]docetaxel). The objective of this study was to investigate whether a [(11)C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel.

Experimental Design: Docetaxel-naïve lung cancer patients underwent 2 [(11)C]docetaxel PET scans; one after bolus injection of [(11)C]docetaxel and another during combined infusion of [(11)C]docetaxel and a therapeutic dose of docetaxel (75 mg·m(-2)).

Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-HT4 receptor.

Background: Serotonin 5-HT4 receptor (5-HT4-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-HT4-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-HT4-R agonist, was selected.

Tumour imaging by Positron Emission Tomography using fluorinase generated 5-[¹⁸F]fluoro-5-deoxyribose as a novel tracer.

Introduction: 5-[(18)F]Fluoro-5-deoxyribose ([(18)F]FDR) 3 was prepared as a novel monosaccharide radiotracer in a two-step synthesis using the fluorinase, a C-F bond forming enzyme, and a nucleoside hydrolase. The resulting [(18)F]FDR 3 was then explored as a radiotracer for imaging tumours (A431 human epithelial carcinoma) by positron emission tomography in a mice model.

Methods: 5-[(18)F]Fluoro-5-deoxyribose ([(18)F]FDR) 3, was prepared by incubating S-adenosyl-L-methionine (SAM) and [(18)F]fluoride with the fluorinase enzyme, and then incubating the product of this reaction, [(18)F]-5'-fluoro-5'-deoxadenosine ([(18)F]FDA) 2, with an adenosine hydrolase to generate [(18)F]FDR 3.

[¹¹C]Sorafenib: radiosynthesis and preclinical evaluation in tumor-bearing mice of a new TKI-PET tracer.

Introduction: Tyrosine kinase inhibitors (TKIs) like sorafenib are important anticancer therapeutics with thus far limited treatment response rates in cancer patients. Positron emission tomography (PET) could provide the means for selection of patients who might benefit from TKI treatment, if suitable PET tracers would be available. The aim of this study was to radiolabel sorafenib (1) with carbon-11 and to evaluate its potential as TKI-PET tracer in vivo.

[11C]AF150(S), an agonist PET ligand for M1 muscarinic acetylcholine receptors.

Background: The M1 muscarinic acetylcholine receptor (M1ACh-R) is a G protein-coupled receptor that can occur in interconvertible coupled and uncoupled states. It is enriched in the basal ganglia, hippocampus, olfactory bulb, and cortical areas, and plays a role in motor and cognitive functions. Muscarinic M1 agonists are potential therapeutic agents for cognitive disorders.

Evaluation of the novel folate receptor ligand [18F]fluoro-PEG-folate for macrophage targeting in a rat model of arthritis.

Introduction: Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[11C]PK11195 and positron emission tomography (PET). Images, however, also showed significant peri-articular background activity.

Tariquidar and elacridar are dose-dependently transported by P-glycoprotein and Bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study.

Elacridar (ELC) and tariquidar (TQD) are generally thought to be nontransported inhibitors of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), but recent data indicate that they may also be substrates of these multidrug transporters (MDTs). The present study was designed to investigate potential transport of ELC and TQD by MDTs at the blood-brain barrier at tracer doses as used in positron emission tomography (PET) studies. We performed PET scans with carbon-11-labeled ELC and TQD before and after MDT inhibition in wild-type and transporter-knockout mice as well as in in vitro transport assays in MDT-overexpressing cells.

Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia.

Objective: To examine the relationships between apolipoprotein E (APOE) ε4 dose and in vivo distributions of both fibrillary amyloid burden and glucose metabolism in the same Alzheimer disease dementia patients, selected for abnormal amyloid imaging.

Methods: Twenty-two APOE ε4 negative, 40 heterozygous, and 22 homozygous Alzheimer disease dementia patients underwent dynamic (90 minutes) [(11)C]Pittsburgh compound B (PIB) and static [(18)F]fluorodeoxyglucose (FDG) PET scans. Parametric nondisplaceable binding potential images of [(11)C]PIB and standardized uptake value ratio images of [(18)F]FDG were generated using cerebellar gray matter as reference tissue.

Amyloid and its association with default network integrity in Alzheimer's disease.

The purpose of this study was to investigate the association between functional connectivity and β-amyloid depositions in the default mode network (DMN) in Alzheimer's disease (AD), patients with mild cognitive impairment (MCI), and healthy elderly. Twenty-five patients with AD, 12 patients with MCI, and 18 healthy controls were included in the study. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in the DMN.

Impact of molecular imaging on the diagnostic process in a memory clinic.

Background: [(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population.

Methods: One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening.

Altered GABAA receptor density and unaltered blood-brain barrier transport in a kainate model of epilepsy: an in vivo study using 11C-flumazenil and PET.

Unlabelled: The aim of the present study was to investigate if flumazenil blood-brain barrier transport and binding to the benzodiazepine site on the γ-aminobutyric acid A (GABA(A)) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)-mediated efflux of flumazenil at the blood-brain barrier may confound interpretation of (11)C-flumazenil PET in epilepsy.

Methods: The transport of flumazenil across the blood-brain barrier and the binding to the benzodiazepine site on the GABA(A) receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive (11)C-flumazenil PET scans, each one lasting 30 min.

Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status.

Purpose: To evaluate whether, in patients with non-small cell lung carcinoma (NSCLC), tumor uptake of [(11)C]erlotinib can be quantified and imaged using positron emission tomography and to assess whether the level of tracer uptake corresponds with the presence of activating tumor EGF receptor (EGFR) mutations.

Experimental Design: Ten patients with NSCLCs, five with an EGFR exon 19 deletion, and five without were scanned twice (test retest) on the same day with an interval of at least 4 hours. Each scanning procedure included a low-dose computed tomographic scan, a 10-minute dynamic [(15)O]H(2)O scan, and a 1-hour dynamic [(11)C]erlotinib scan.

Reproducible Analysis of Rat Brain PET Studies Using an Additional [(18)F]NaF Scan and an MR-Based ROI Template.

Background. An important step in the analysis of positron emission tomography (PET) studies of the brain is the definition of regions of interest (ROI). Image coregistration, ROI analysis, and quantification of brain PET data in small animals can be observer dependent.

Microglial activation in Alzheimer's disease: an (R)-[¹¹C]PK11195 positron emission tomography study.

Unlabelled: Inflammatory mechanisms, like microglial activation, could be involved in the pathogenesis of Alzheimer's disease (AD). (R)-[(11)C]PK11195 (1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide), a positron emission tomography (PET) ligand, can be used to quantify microglial activation in vivo. The purpose of this study was to assess whether increased (R)-[(11)C]PK11195 binding is present in AD and mild cognitive impairment (MCI), currently also known as "prodromal AD.

PET imaging with small-molecule tyrosine kinase inhibitors: TKI-PET.

The discovery and increased understanding of tumor targets has led to the development and approval of 12 small molecule tyrosine kinase inhibitors (TKIs). Despite tremendous efforts in TKI development, treatment efficacies with these therapeutics are still too low and improvements require a personalized medicine approach. Positron emission tomography (PET) with radiolabeled TKIs (TKI-PET) is a tracking, quantification and imaging method, which provides a unique understanding of the behavior of these drugs in vivo and of the interaction with their target(s).

[11C]phenytoin revisited: synthesis by [11C]CO carbonylation and first evaluation as a P-gp tracer in rats.

Background: At present, several positron emission tomography (PET) tracers are in use for imaging P-glycoprotein (P-gp) function in man. At baseline, substrate tracers such as R-[11C]verapamil display low brain concentrations with a distribution volume of around 1. [11C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline.

No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds.

Decreased blood-brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[(11)C]verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[(11)C]verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA.

Amyloid burden and metabolic function in early-onset Alzheimer's disease: parietal lobe involvement.

Alzheimer's disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimer's disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimer's disease and 20 healthy controls.