In vivo imaging of brain androgen receptors in rats: a [18F]FDHT PET study

AbstractIntroductionSteroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT) to image AR expression in the brain.MethodsMale Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [18F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution.ResultsPET imaging and ex vivo biodistribution studies showed low [18F]FDHT uptake in all brain regions, except pituitary. [18F]FDHT uptake in the surrounding cranial bones was high and increased over time. [18F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [18F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone.ConclusionThe results of this study indicate that imaging of AR availability in rat brain with [18F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [18F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [18F]FDHT PET in this study

Scintigraphic Imaging of HSVtk Expression in Gene Therapy

Suicide gene therapy is under investigation as a treatment for cancer. In this therapy, a suicide gene is introduced into tumor cells, enabling the conversion of a prodrug into a toxic metabolite that selectively kills the transfected tumor cells. In the most investigated strategy, the herpes simplex virus thymidine kinase (HSVtk) suicide gene is used in combination with the prodrug ganciclovir. To assess the efficiency and safety of gene therapy protocols, a noninvasive method to assay the magnitude, kinetics and spatial distribution of transgene expression is essential. Imaging methods for repetitive monitoring of HSVtk transgene expression in living animals and humans, using single photon emission computed tomography (SPECT) or positron emission tomography (PET), have been developed. For many therapeutic genes, however, no imaging method is available. In these cases, reporter genes can be applied. Expression of the therapeutic gene can be determined indirectly by imaging a reporter gene, like HSVtk, that is linked to the therapeutic gene. Reporter genes can also be applied to monitor the expression of endogenous genes and to track the fate of transplanted cells. This paper presents an updated review on the progress in the field of non-invasive nuclear imaging of HSVtk transgene expression in gene therapy

Nuclear Imaging of Inflammation in Neurologic and Psychiatric Disorders

Cerebral inflammation is a common phenomenon during the progression of neurodegenerative diseases. In general, neurodegenerative diseases have unpredictable clinical courses and timely effective treatment is not available. For effective clinical trials on new drugs, suitable surrogate markers to monitor disease progression are required. The extent of cerebral inflammation could be such a surrogate marker. Nuclear imaging techniques, like positron emission tomography (PET) and single photon emission computed tomography (SPECT), have been applied to monitor inflammatory processes in patients. Neuroinflammation is accompanied by a variety of physiological changes, such as changes in cerebral glucose metabolism and perfusion, cyclooxygenase-2 overexpression and microglia activation. Nuclear imaging has utilized these physiological changes to visualize the inflammatory process in various chronic or acute neurodegenerative diseases. Expression of the peripheral benzodiazepine receptor in activated microglia proved a suitable specific marker to detect neuroinflammation. Currently, radiolabeled COX-2 inhibitors are under investigation for this purpose. The causative of neuroinflammation is often unknown, but the herpes simplex virus (HSV), for example, has been implicated in several neurodegenerative diseases. Recently, antiviral agents and antibiotics have been prepared that might be applicable to discriminate specific viral or bacterial infections. These radiolabeled compounds could also be used to monitor the drug pharmacokinetics noninvasively with PET. This review summarizes the progress that has been made in nuclear imaging of neuroinflammation in neuropsychiatric diseases

PET Tracers for Mapping Adenosine Receptors as Probes for Diagnosis of CNS Disorders

Adenosine is an endogenous modulator of several physiological functions in the central nervous system (CNS). The effect is mediated by a receptor family that consists of at least four subtypes: A1, A2A, A2B and A3 receptors. The adenosine receptors play a role in neurological and psychiatric disorders such as Alzheimers disease, Parkinsons disease, epilepsy and schizophrenia. Knowledge on adenosine receptor densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Positron emission tomography (PET) offers a non-invasive tool to investigate these features in vivo, provided that suitable radiopharmaceuticals are available. As a consequence of the development of xanthine-type adenosine receptor antagonists with high affinity and high selectivity, several PET ligands labeled with carbon-11 (half-life of 20.4 min) and fluorine-18 (half-life of 109.8 min) have been proposed for mapping the adenosine A1 and A2A receptors (A1R and A2AR, respectively) and the adenosine uptake site in the CNS since 1995. Later non-xanthine-type antagonists for A2AR were radiolabeled. So far two tracers for A1R, [18F]CPFPX and [11C]MPDX, and a tracer for A2AR, [11C]TMSX (also called [11C]KF18446), have been applied to humans. For the other subtypes and the adenosine uptake site no suitable radioligands have been developed yet. This paper gives an overview of the current status on PET tracers for mapping adenosine receptors and the development of new compounds that may lead to new PET tracers

Chiral diethanolamines and their lithium alcoholates as catalysts in the enantioselective alkylation of benzaldehyde by diethylzinc

The enantioselective alkylation of benzaldehyde by diethylzinc in the presence of catalytic amounts of bis-erythro diethanolamines and their lithium alcoholates was studied. The extent of asymmetric induction was found to depend strongly upon subtle changes in the structure of the catalyst used

Stereoselective reduction of prochiral ketones, using aluminum hydride reagents prepared from LiAlH4and chiral diethanolamines

The asymmetric reduction of prochiral ketones to chiral secondary alcohols by LiAlH4, modified with optically active diethanolamines, was studied. Asymmetric inductions of up to 94% were obtained with these reagents. The stereoselectivity of the reaction was found to depend both upon the temperature at which the reduction was performed and upon the conditions under which the chiral aluminum hydride reagent had been prepared. By changing the substituents at the carbon atom α to nitrogen in the chiral auxiliary, either the (R)- or the (S)-enantiomer of the secondary alcohol could be obtained in excess

An 8 week periodized mesocycle leading to a national level weightlifting competition

Item does not contain fulltex