Structure-Activity Relationships and Evaluation of 2-(Heteroaryl-cycloalkyl)-1-indoles as Tauopathy Positron Emission Tomography Radiotracers.

Structure-activity relationship studies were performed on a library of synthesized compounds based on previously identified tau ligands. The top 13 new compounds had values in the range of 5-14 nM in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) post-mortem brain tissues. One of the more promising new compounds ([H]) bound with high affinity in AD, PSP, and CBD tissues ('s = 1-1.

Kinetic modeling of the monoamine oxidase-B radioligand [F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [F]()-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression.

Imaging Cortical Dopamine Transmission in Cocaine Dependence: A [C]FLB 457-Amphetamine Positron Emission Tomography Study.

Background: Positron emission tomography studies have demonstrated less dopamine D receptor availability and blunted psychostimulant-induced dopamine release in cocaine-dependent subjects (CDSs). No studies in CDSs have reported the in vivo status of D and dopamine release in the cortex. Basic and functional imaging studies suggest a role for prefrontal cortical dopaminergic abnormalities in impaired executive function and relapse in cocaine dependence.

Synthesis and preliminary evaluation of an ¹⁸F-labeled oleic acid analog for PET imaging of fatty acid uptake and metabolism.

Introduction: Imaging fatty acid uptake and utilization has broad impact in investigating myocardial diseases, hepatic functions, tumor progression, and the metabolic state of adipose tissue. The SPECT tracer (123)I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) is a clinically used nuclear medicine tracer to image myocardial uptake of fatty acid. Although ((18)F-5) has been in clinical use for PET imaging of adipose tissue as well as the myocardium, here we developed a click oleate analog to compare to FTO, with the goal of improved stability to defluorination and suitability for imaging myocardial uptake and oxidation of fatty acids.

Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials.

Objective: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using (11)C-Pittsburgh compound B ((11)C-PiB)-PET.

Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks.

Decreased vesicular monoamine transporter type 2 availability in the striatum following chronic cocaine self-administration in nonhuman primates.

Background: Consistent with postmortem data, in a recent positron emission tomography study, we demonstrated less [(11)C]-(+)-dihydrotetrabenazine ([(11)C]DTBZ) binding to striatal vesicular monoamine transporter type 2 (VMAT2) in cocaine abusers compared with control subjects. A major limitation of these between-group comparison human studies is their inability to establish a causal relationship between cocaine abuse and lower VMAT2. Furthermore, studies in rodents that evaluated VMAT2 binding before and after cocaine self-administration do not support a reduction in VMAT2.

Cocaine abuse in humans is not associated with increased microglial activation: an 18-kDa translocator protein positron emission tomography imaging study with [11C]PBR28.

Basic science investigations have consistently shown that repeated exposure to psychostimulant drugs, such as cocaine, activate the immune response and lead to inflammatory changes in the brain. No previous in vivo studies have confirmed this observation in chronic cocaine-abusing humans. To test this hypothesis, we used positron emission tomography imaging to measure the binding of [(11)C]PBR28 to the 18 kDa translocator protein (TSPO), a marker for microglial activation in a group of 15 recently abstinent cocaine abusers and 17 matched healthy controls.

Decreased prefrontal cortical dopamine transmission in alcoholism.

Objective: Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence.

Method: To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects.

Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products.

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin.

Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents.

To continue our efforts toward the development of (99m)Tc PiB analogs, we have synthesized 24 neutral and lipophilic Re (as a surrogate of (99m)Tc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to Aβ1-40 fibrils. These Re complexes were designed and synthesized via the integrated approach, so their (99m)Tc analogs would have a greater chance of crossing the blood-brain barrier. While the lipophilicities (logPC18=1.

Utility of 3'-[(18)F]fluoro-3'-deoxythymidine as a PET tracer to monitor response to gene therapy in a xenograft model of head and neck carcinoma.

Noninvasive imaging methodologies are needed to assess treatment responses to novel molecular targeting approaches for the treatment of squamous cell carcinoma of the head and neck (SCCHN). Computer tomography and magnetic resonance imaging do not effectively distinguish tumors from fibrotic tissue commonly associated with SCCHN tumors. Positron emission tomography (PET) offers functional non-invasive imaging of tumors.

Improved working memory but no effect on striatal vesicular monoamine transporter type 2 after omega-3 polyunsaturated fatty acid supplementation.

Studies in rodents indicate that diets deficient in omega-3 polyunsaturated fatty acids (n-3 PUFA) lower dopamine neurotransmission as measured by striatal vesicular monoamine transporter type 2 (VMAT2) density and amphetamine-induced dopamine release. This suggests that dietary supplementation with fish oil might increase VMAT2 availability, enhance dopamine storage and release, and improve dopamine-dependent cognitive functions such as working memory. To investigate this mechanism in humans, positron emission tomography (PET) was used to measure VMAT2 availability pre- and post-supplementation of n-3 PUFA in healthy individuals.

In vivo evidence for low striatal vesicular monoamine transporter 2 (VMAT2) availability in cocaine abusers.

Objective: Positron emission tomography (PET) imaging studies in cocaine abusers have shown that low dopamine release in the striatum following an amphetamine challenge is associated with higher relapse rates. One possible mechanism that might lead to lower amphetamine-induced dopamine release is low availability of dopamine storage vesicles in the presynaptic terminals for release. Consistent with this hypothesis, postmortem studies have shown low levels of vesicular monoamine transporter, type 2 (VMAT2), the membrane protein that regulates the size of the vesicular dopamine pool, in cocaine abusers relative to healthy subjects.

Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study.

Objective: Positron emission tomography (PET) studies performed with [(11) C]raclopride have consistently reported lower binding to D(2/3) receptors and lower amphetamine-induced dopamine (DA) release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D(2/3) antagonist radiotracers such as [(11) C]raclopride is the failure to provide information that is specific to D(2/3) receptors configured in a state of high affinity for the agonists (i.e.

Human biodistribution and dosimetry of the PET radioligand [¹¹C]flumazenil (FMZ).

Purpose: We measure the whole-body distribution of IV injected [¹¹C]Flumazenil (FMZ) as a function of time in adult subjects and determine the absorbed radiation doses.

Procedures: After injection with 770 MBq of [¹¹C]FMZ (nominal), each of six subjects underwent nine consecutive whole body PET scans. Twelve source organs were identified using PET attenuation and emission images.

A [polycation:heparin] complex releases growth factors with enhanced bioactivity.

Growth factors are potent molecules that regulate cell functions including survival, self renewal, differentiation and proliferation. High-efficacy delivery of growth factors will be a powerful tool for regenerative medicine. Decades of intense research have significantly advanced the field of controlled delivery.