Modular Strategies for PET Imaging Agents

In recent years, modular and simplified chemical and biological strategies have been developed for the synthesis and implementation of positron emission tomography (PET) radiotracers. New developments in bioconjugation and synthetic methodologies, in combination with advances in macromolecular delivery systems and gene-expression imaging, reflect a need to reduce radiosynthesis burden in order to accelerate imaging agent development. These new approaches, which are often mindful of existing infrastructure and available resources, are anticipated to provide a more approachable entry point for researchers interested in using PET to translate in vitro research to in vivo imaging.Chemistry and Chemical Biolog

Nickel-Mediated Oxidative Fluorination for PET with Aqueous [18F^{18}F] Fluoride

A one-step oxidative fluorination for carbon–fluorine bond formation from well-defined nickel complexes with oxidant and aqueous fluoride is presented, which enables a straightforward and practical $^{18}F$ late-stage fluorination of complex small molecules with potential for PET imaging.Chemistry and Chemical Biolog

Visualizing Epigenetics: Current Advances and Advantages in HDAC PET Imaging Techniques

Abnormal gene regulation as a consequence of flawed epigenetic mechanisms may be central to the initiation and persistence of many human diseases. However, the association of epigenetic dysfunction with disease and the development of therapeutic agents for treatment are slow. Developing new methodologies used to visualize chromatin-modifying enzymes and their function in the human brain would be valuable for the diagnosis of brain disorders and drug discovery. We provide an overview of current invasive and noninvasive techniques for measuring expression and functions of chromatin-modifying enzymes in the brain, emphasizing tools applicable to histone deacetylase (HDAC) enzymes as a leading example. The majority of current techniques are invasive and difficult to translate to what is happening within a human brain in vivo. However, recent progress in molecular imaging provides new, noninvasive ways to visualize epigenetics in the human brain. Neuroimaging tool development presents a unique set of challenges in order to identify and validate CNS radiotracers for HDACs and other histone-modifying enzymes. We summarize advances in the effort to image HDACs and HDAC inhibitory effects in the brain using positron emission tomography (PET) and highlight generalizable techniques that can be adapted to investigate other specific components of epigenetic machinery. Translational tools like neuroimaging by PET and magnetic resonance imaging provide the best way to link our current understanding of epigenetic changes with in vivo function in normal and diseased brains. These tools will be a critical addition to ex vivo methods to evaluate – and intervene – in CNS dysfunction.Chemistry and Chemical Biolog

Psychomotor Impairment Detection via Finger Interactions with a Computer Keyboard During Natural Typing

Modern digital devices and appliances are capable of monitoring the timing of button presses, or finger interactions in general, with a sub-millisecond accuracy. However, the massive amount of high resolution temporal information that these devices could collect is currently being discarded. Multiple studies have shown that the act of pressing a button triggers well defined brain areas which are known to be affected by motor-compromised conditions. In this study, we demonstrate that the daily interaction with a computer keyboard can be employed as means to observe and potentially quantify psychomotor impairment. We induced a psychomotor impairment via a sleep inertia paradigm in 14 healthy subjects, which is detected by our classifier with an Area Under the ROC Curve (AUC) of 0.93/0.91. The detection relies on novel features derived from key-hold times acquired on standard computer keyboards during an uncontrolled typing task. These features correlate with the progression to psychomotor impairment (p < 0.001) regardless of the content and language of the text typed, and perform consistently with different keyboards. The ability to acquire longitudinal measurements of subtle motor changes from a digital device without altering its functionality may allow for early screening and follow-up of motor-compromised neurodegenerative conditions, psychological disorders or intoxication at a negligible cost in the general population.Comunidad de Madri

Virtually Instantaneous, Room-Temperature [11C]-Cyanation Using Biaryl Phosphine Pd(0) Complexes

A new radiosynthetic protocol for the preparation of [[superscript 11]C]aryl nitriles has been developed. This process is based on the direct reaction of in situ prepared L·Pd(Ar)X complexes (L = biaryl phosphine) with [[superscript 11]C]HCN. The strategy is operationally simple, exhibits a remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity compared to previously reported systems. With this procedure, a variety of [[superscript 11]C]nitrile-containing pharmaceuticals were prepared with high radiochemical efficiency.National Institutes of Health (U.S.) (NIH GM46059)National Science Foundation (U.S.) (NSF predoctoral fellowship (2010094243))Amgen Inc. (Educational donation)National Institutes of Health (U.S.) (NIH-NIDA postdoctoral fellowship (2T32DA015036)

Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [11C]CH3I to label RIF and [11C]HCN to label INH and PZA. Following iv administration, INH, PZA, RIF, and/or their radiolabeled metabolites clear rapidly from many tissues; however, INH, PZA, and/or their radiolabeled metabolites accumulate in the bladder while RIF and/or its radiolabeled metabolites accumulates in the liver and gall bladder, consistent with the known routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood−brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth of Mycobacterium tuberculosis (MTB). The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain and pave the way for imaging the distribution of the pathogen in vivo.Chemistry and Chemical Biolog

Evaluation of [11C]metergoline as a PET Radiotracer for 5HTR in Nonhuman Primates

Metergoline, a serotonin receptor antagonist, was labeled with carbon-11 in order to evaluate its pharmacokinetics and distribution in non-human primates using positron emission tomography. [11C]Metergoline had moderate brain uptake and exhibited heterogeneous specific binding, which was blocked by pretreatment with metergoline and altanserin throughout the cortex. Non-specific binding and insensitivity to changes in synaptic serotonin limit its potential as a PET radiotracer. However, the characterization of [11C]metergoline pharmacokinetics and binding in the brain and peripheral organs using PET improves our understanding of metergoline drug pharmacology.Chemistry and Chemical Biolog

Cue-Induced Dopamine Release Predicts Cocaine Preference: Positron Emission Tomography Studies in Freely Moving Rodents

Positron emission tomography studies in drug-addicted patients have shown that exposure to drug-related cues increases striatal dopamine, which displaces binding of the D2 ligand, [11C]-raclopride. However, it is not known if animals will also show cue-induced displacement of [11C]-raclopride binding. In this study, we use [11C]-raclopride imaging in awake rodents to capture cue-induced changes in dopamine release associated with the conditioned place preference model of drug craving. Ten animals were conditioned to receive cocaine in a contextually distinct environment from where they received saline. Following conditioning, each animal was tested for preference and then received two separate [11C]-raclopride scans. For each scan, animals were confined to the cocaine and/or the saline-paired environment for the first 25 min of uptake, after which they were anesthetized and scanned. [11C]-raclopride uptake in the saline-paired environment served as a within-animal control for uptake in the cocaine-paired environment. Cocaine produced a significant place preference (p = 0.004) and exposure to the cocaine-paired environment decreased [11C]-raclopride binding relative to the saline-paired environment in both the dorsal (20%; p < 0.002) and ventral striatum (22%; p < 0.05). The change in [11C]-raclopride binding correlated with preference in the ventral striatum (R2 = −0.87; p = 0.003). In this region, animals who showed little or no preference exhibited little or no change in [11C]-raclopride binding in the cocaine-paired environment. This noninvasive procedure of monitoring neurochemical events in freely moving, behaving animals advances preclinical molecular imaging by interrogating the degree to which animal models reflect the human condition on multiple dimensions, both biological and behavioral.Chemistry and Chemical Biolog

Noninvasive Determination of 2-[18F]-Fluoroisonicotinic Acid Hydrazide Pharmacokinetics by Positron Emission Tomography in Mycobacterium tuberculosis-Infected Mice

Tuberculosis (TB) is a global pandemic requiring sustained therapy to facilitate curing and to prevent the emergence of drug resistance. There are few adequate tools to evaluate drug dynamics within infected tissues in vivo. In this report, we evaluated a fluorinated analog of isoniazid (INH), 2-[18F]fluoroisonicotinic acid hydrazide (2-[18F]-INH), as a probe for imaging Mycobacterium tuberculosis-infected mice by dynamic positron emission tomography (PET). We developed a tail vein catheter system to safely deliver drugs to M. tuberculosis aerosol-infected mice inside sealed biocontainment devices. Imaging was rapid and noninvasive, and it could simultaneously visualize multiple tissues. Dynamic PET imaging demonstrated that 2-[18F]-INH was extensively distributed and rapidly accumulated at the sites of infection, including necrotic pulmonary TB lesions. Compared to uninfected animals, M. tuberculosis-infected mice had a significantly higher PET signal within the lungs (P 0.85), suggesting that 2-[18F]-INH accumulated at the site of the pulmonary infection. Furthermore, our data indicated that similar to INH, 2-[18F]-INH required specific activation and accumulated within the bacterium. Pathogen-specific metabolism makes positron-emitting INH analogs attractive candidates for development into imaging probes with the potential to both detect bacteria and yield pharmacokinetic data in situ. Since PET imaging is currently used clinically, this approach could be translated from preclinical studies to use in humans.Chemistry and Chemical Biolog

Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation

New chemistry methods for the synthesis of radiolabeled small molecules have the potential to impact clinical positron emission tomography (PET) imaging, if they can be successfully translated. However, progression of modern reactions from the stage of synthetic chemistry development to the preparation of radiotracer doses ready for use in human PET imaging is challenging and rare. Here we describe the process of and the successful translation of a modern palladium-mediated fluorination reaction to non-human primate (NHP) baboon PET imaging–an important milestone on the path to human PET imaging. The method, which transforms [18F]fluoride into an electrophilic fluorination reagent, provides access to aryl–18F bonds that would be challenging to synthesize via conventional radiochemistry methods.Chemistry and Chemical Biolog