The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

The neuropeptide melanin-concentrating hormone (MCH) plays a key role in energy maintenance by decreasing energy expenditure and stimulating feeding behavior. Furthermore, it is involved in diabetes, gut inflammation, sleep, depression, and cilia beat function. The biological function of MCH is mediated by two G-protein coupled receptors, MCH receptor 1 and 2 (MCHR1 and MCHR2). Since only the MCHR1 is functional in rodents, the physiological importance of MCHR2 remains unknown due to the lack of appropriate animal models. The involvement of the MCHergic system in a variety of pathologies, especially endocrinological diseases, such as obesity and diabetes, makes it interesting as a new target to treat human disorders. Many pharmaceutical companies have pursued the development of MCHR1 antagonists for the treatment of obesity. Moreover, positron emission tomography (PET) tracers targeting the MCHR1 have been developed in order to gain a deeper understanding of the role and distribution of the MCHR1. As a high-end technique, PET allows noninvasive in vivo visualization and quantification of receptor systems, as well as monitoring and following hormone receptor status and related pathologies. Therefore, a MCHR1 PET tracer could help to guide pharmacological intervention via the MCHR1

Folgen und Reihen - ein Vergleich von verschiedenen Schultypen (AHS, HTL, HAK) anhand einer Schulbuchanalyse

Es werden verschiedene Schulbücher von AHS, HAK und HTL miteinander zu dem Thema "Folgen und Reihen" verglichen und Unterschiede verdeutlicht

Parameter evaluation and fully-automated radiosynthesis of [11C]harmine for imaging of MAO-A for clinical trials

AbstractThe aim of the present study was the evaluation and automation of the radiosynthesis of [11C]harmine for clinical trials. The following parameters have been investigated: amount of base, precursor concentration, solvent, reaction temperature and time. The optimum reaction conditions were determined to be 2–3mg/mL precursor activated with 1eq. 5M NaOH in DMSO, 80°C reaction temperature and 2min reaction time. Under these conditions 6.1±1GBq (51.0±11% based on [11C]CH3I, corrected for decay) of [11C]harmine (n=72) were obtained. The specific activity was 101.32±28.2GBq/µmol (at EOS). All quality control parameters were in accordance with the standards for parenteral human application. Due to its reliability and high yields, this fully-automated synthesis method can be used as routine set-up

In vivo P-glycoprotein function before and after epilepsy surgery

Objectives: To study the functional activity of the multidrug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier of patients with temporal lobe epilepsy using (R)-[11C]verapamil (VPM)-PET before and after temporal lobe surgery to assess whether postoperative changes in seizure frequency and antiepileptic drug load are associated with changes in Pgp function. Methods: Seven patients with drug-resistant temporal lobe epilepsy underwent VPM-PET scans pre- and postsurgery. Patients were followed up for a median of 6 years (range 4–7) after surgery. Pgp immunoreactivity in surgically resected hippocampal specimens was determined with immunohistochemistry. Results: Optimal surgical outcome, defined as seizure freedom and withdrawal of antiepileptic drugs, was associated with higher temporal lobe Pgp function before surgery, higher Pgp-positive staining in surgically resected hippocampal specimens, and reduction in global Pgp function postoperatively, compared with nonoptimal surgery outcome. Conclusions: The data from our pilot study suggest that Pgp overactivity in epilepsy is dynamic, and complete seizure control and elimination of antiepileptic medication is associated with reversal of overactivity, although these findings will require confirmation in a larger patient cohort

Cyclotrons Operated for Nuclear Medicine and Radiopharmacy in the German Speaking D-A-CH Countries: An Update on Current Status and Trends

Background: Cyclotrons form a central infrastructure and are a resource of medical radionuclides for the development of new radiotracers as well as the production and supply of clinically established radiopharmaceuticals for patient care in nuclear medicine. Aim: To provide an updated overview of the number and characteristics of cyclotrons that are currently in use within radiopharmaceutical sciences and for the development of radiopharmaceuticals to be used for patient care in Nuclear Medicine in Germany (D), Austria (A) and Switzerland (CH). Methods: Publicly available information on the cyclotron infrastructure was (i) consolidated and updated, (ii) supplemented by selective desktop research and, last but not least, (iii) validated by members of the committee of the academic “Working Group Radiochemistry and Radiopharmacy” (AGRR), consisting of radiochemists and radiopharmacists of the D-A-CH countries and belonging to the German Society of Nuclear Medicine (DGN), as well as the Radiopharmaceuticals Committee of the DGN. Results: In total, 42 cyclotrons were identified that are currently being operated for medical radionuclide production for imaging and therapy in Nuclear Medicine clinics, 32 of them in Germany, 4 in Austria and 6 in Switzerland. Two thirds of the cyclotrons reported (67%) are operated by universities, university hospitals or research institutions close to a university hospital, less by/in cooperation with industrial partners (29%) or a non-academic clinic/ PET-center (5%). Most of the cyclotrons (88%) are running with up to 18 MeV proton beams, which is sufficient for the production of the currently most common cyclotron-based radionuclides for PET imaging. Discussion: The data presented provide an academically-updated overview of the medical cyclotrons operated for the production of radiopharmaceuticals and their use in Nuclear Medicine in the D-A-CH countries. In this context, we discuss current developments and trends with a view to the cyclotron infrastructure in these countries, with a specific focus on organizational aspects

Preclinical In Vitro

Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of [F]FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of [F]FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as 2.3-fold higher accumulation of [F]FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1) poor conservation of target expression in xenografts and (2) unfavorable pharmacokinetics of [F]FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using [F]FE@SUPPY.(VLID)481541

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia