Fully Automated Production of ((()-1-Carboxy-5-(6-([F]fluoro)-2-methoxynicotinamido)pentyl)carbamoyl)-l-glutamic Acid ([F]JK-PSMA-7).

The radiotracer [F]JK-PSMA-7, a prostate cancer imaging agent for positron emission tomography (PET), was previously synthesized by indirect radiofluorination using an F-labeled active ester as a prosthetic group, which had to be isolated and purified before it could be linked to the pharmacologically active Lys-urea-Glu motif. Although this procedure could be automated on two-reactor modules like the GE TRACERLab FX2N (FXN) to afford the tracer in modest radiochemical yields (RCY) of 18-25%, it is unsuitable for cassette-based systems with a single reactor. To simplify implementation on an automated synthesis module, the radiosynthesis of [F]JK-PSMA-7 was devised as a one-pot, two-step reaction.

Preparation and Preclinical Evaluation of F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1).

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib.

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.

mGluR and GABA receptor-specific parametric PET atlas construction-PET/MR data processing pipeline, validation, and application.

The glutamate and γ-aminobutyric acid neuroreceptor subtypes mGluR and GABA are hypothesized to be involved in the development of a variety of psychiatric diseases. However, detailed information relating to their in vivo distribution is generally unavailable. Maps of such distributions could potentially aid clinical studies by providing a reference for the normal distribution of neuroreceptors and may also be useful as covariates in advanced functional magnetic resonance imaging (MR) studies.

mGluR5 binding changes during a mismatch negativity task in a multimodal protocol with [C]ABP688 PET/MR-EEG.

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BP) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol.

Comparison of the Amyloid Load in the Brains of Two Transgenic Alzheimer's Disease Mouse Models Quantified by Florbetaben Positron Emission Tomography.

Alzheimer's disease (AD) is characterized by formation of amyloid plaques and neurofibrillary tangles in the brain, which can be mimicked by transgenic mouse models. Here, we report on the characterization of amyloid load in the brains of two transgenic amyloidosis models using positron emission tomography (PET) with florbetaben (FBB), an F-labeled amyloid PET tracer routinely used in AD patients. Young, middle-aged, and old homozygous APP/PS1 mice (ARTE10), old hemizygous APPswe/PS1ΔE9, and old wild-type control mice were subjected to FBB PET using a small animal PET/computed tomography scanner.

Radiosynthesis and Biological Evaluation of [F]R91150, a Selective 5-HT Receptor Antagonist for PET-Imaging.

Serotonergic 5-HT receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for quantification of receptor densities and receptor occupancy for therapy evaluation.

Excitatory-inhibitory balance within EEG microstates and resting-state fMRI networks: assessed via simultaneous trimodal PET-MR-EEG imaging.

The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and γ-aminobutyric acid (GABA) and the receptor availability (RA) of GABA and mGluR5, remains unexplored. This research investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data.

Expanding PET-applications in life sciences with positron-emitters beyond fluorine-18.

Positron-emission-tomography (PET) has become an indispensable diagnostic tool in modern nuclear medicine. Its outstanding molecular imaging features allow repetitive studies on one individual and with high sensitivity, though no interference. Rather few positron-emitters with near favourable physical properties, i.

Radiosynthesis and evaluation of F-labeled dopamine D-receptor ligands.

Introduction: The dopamine D receptor (DR) has attracted considerable attention as potential target for the treatment of a broad range of central nervous system disorders. Although many efforts have been made to improve the performance of putative radioligand candidates, there is still a lack of DR selective tracers suitable for in vivo PET imaging. Thus, the objective of this work was to develop a D-selective PET ligand for clinical applications.

Bolus infusion scheme for the adjustment of steady state [C]Flumazenil levels in the grey matter and in the blood plasma for neuroreceptor imaging.

The use of hybrid PET/MR imaging facilitates the simultaneous investigation of challenge-related changes in ligand binding to neuroreceptors using PET, while concurrently measuring neuroactivation or blood flow with MRI. Having attained a steady state of the PET radiotracer using a bolus-infusion protocol, it is possible to observe alterations in ligand neuroreceptor binding through changes in distribution volumes. Here, we present an iterative procedure for establishing an administration scheme to obtain steady state [C]flumazenil concentrations in grey matter in the human brain.

High uptake of Ga-PSMA and F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes.

Background: Recent studies reported on high uptake of the PSMA ligands [Ga]HBED-CC (Ga-PSMA) and F-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of Ga-PSMA and F-DCFPyL in three different rat glioma models.

Methods: F98, 9 L, or U87 rat gliomas were implanted into the brains of 38 rats.

mGluR5 receptor availability is associated with lower levels of negative symptoms and better cognition in male patients with chronic schizophrenia.

Consistent findings postulate disturbed glutamatergic function (more specifically a hypofunction of the ionotropic NMDA receptors) as an important pathophysiologic mechanism in schizophrenia. However, the role of the metabotropic glutamatergic receptors type 5 (mGluR5) in this disease remains unclear. In this study, we investigated their significance (using [ C]ABP688) for psychopathology and cognition in male patients with chronic schizophrenia and healthy controls.

Current trends in the use of O-(2-[F]fluoroethyl)-L-tyrosine ([F]FET) in neurooncology.

The diagnostic potential of PET using the amino acid analogue O-(2-[F]fluoroethyl)-L-tyrosine ([F]FET) in brain tumor diagnostics has been proven in many studies during the last two decades and is still the subject of multiple studies every year. In addition to standard magnetic resonance imaging (MRI), positron emission tomography (PET) using [F]FET provides important diagnostic data concerning brain tumor delineation, therapy planning, treatment monitoring, and improved differentiation between treatment-related changes and tumor recurrence. The pharmacokinetics, uptake mechanisms and metabolism have been well described in various preclinical studies.

Image-Derived Input Functions for Quantification of A Adenosine Receptors Availability in Mice Brains Using PET and [F]CPFPX.

Purpose: imaging for the A adenosine receptors (AARs) with positron emission tomography (PET) using 8-cyclopentyl-3-(3-[F]fluoropropyl)-1-propylxan- thine ([F]CPFPX) has become an important tool for studying physiological processes quantitatively in mice. However, the measurement of arterial input functions (AIFs) on mice is a method with restricted applicability because of the small total blood volume and the related difficulties in withdrawing blood. Therefore, the aim of this study was to extract an appropriate [F]CPFPX image-derived input function (IDIF) from dynamic PET images of mice.

Baeyer-Villiger oxidation tuned to chemoselective conversion of non-activated [ F]fluorobenzaldehydes to [ F]fluorophenols.

A reaction pathway via oxidation of [ F]fluorobenzaldehydes offers a very useful tool for the no-carrier-added radiosynthesis of [ F]fluorophenols, a structural motive of several potential radiopharmaceuticals. A considerably improved chemoselectivity of the Baeyer-Villiger oxidation (BVO) towards phenols was achieved, employing 2,2,2-trifluoroethanol as reaction solvent in combination with Oxone or m-CPBA as oxidation agent. The studies showed the necessity of H SO addition, which appears to have a dual effect, acting as catalyst and desiccant.

Mn-Labelled CDTA-based trimeric complexes as novel bimodal PET/MR probes with high relaxivity.

trans-1,2-Diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA) labelled with a mixture of paramagnetic 55Mn(ii) and β+-emitting 52gMn(ii) offers access to bimodal Positron Emission Tomography/Magnetic Resonance (PET/MR) tracers. To enhance the number of NMR-active nuclei and simultaneously improve the longitudinal relaxivity r1, a complex composed of three CDTA units was designed. Accordingly, a functionalised tris-CDTA-1,3,5-tris-triazolobenzene was prepared and labelled with c.

Labelling with positron emitters of pnicogens and chalcogens.

The increasing importance of the positron emission tomography (PET) in clinical diagnosis led to the development of a multitude of radiotracers labelled with positron-emitting radionuclides of groups 15 (pnicogens) and 16 (chalcogens) of the periodic table of elements. The positron emitters of the endogenous occurring elements nitrogen, phosphorus, oxygen, and sulphur are characterized by very short half-lives compared with the most commonly used PET radionuclides carbon-11 or fluorine-18. Therefore, the potential of their synthesis and possible applications in PET is challenging and limited.

Evaluation of Practical Interpretation Hurdles in 68Ga-PSMA PET/CT in 55 Patients: Physiological Tracer Distribution and Incidental Tracer Uptake.

Purpose: To investigate the physiologic Ga-PSMA distribution and evaluate focal or diffuse radiotracer uptake in nonprostate cancer malignancies and in incidental findings.

Methods: Ga-PSMA PET/CT scans in 55 men performed for prostate cancer (49) or renal cell carcinoma (6) staging were analyzed retrospectively. Two radiologists evaluated the datasets in 2 reading sessions.

Influence of Bevacizumab on Blood-Brain Barrier Permeability and -(2-F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas.

Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using -(2-F-fluoroethyl)-l-tyrosine (F-FET) may be helpful for solving this diagnostic problem.

Influence of blood-brain barrier permeability on O-(2-F-fluoroethyl)-L-tyrosine uptake in rat gliomas.

Purpose: O-(2-F-fluoroethyl)-L-tyrosine (F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on F-FET uptake in two rat glioma models and one human xenograft model.

Methods: F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats.

Synthesis of a Potent Aminopyridine-Based nNOS-Inhibitor by Two Recent No-Carrier-Added (18)F-Labelling Methods.

Nitric oxide (NO), an important multifunctional signaling molecule, is produced by three isoforms of NO-synthase (NOS) and has been associated with neurodegenerative disorders. Selective inhibitors of the subtypes iNOS (inducible) or nNOS (neuronal) are of great interest for decoding neurodestructive key factors, and (18)F-labelled analogues would allow investigating the NOS-function by molecular imaging with positron emission tomography. Especially, the highly selective nNOS inhibitor 6-((3-((3-fluorophenethylamino)methyl)phenoxy)methyl)-4-methylpyridin-2-amine (10) lends itself as suitable compound to be (18)F-labelled in no-carrier-added (n.

Circadian variation of metabotropic glutamate receptor 5 availability in the rat brain.

The metabotrophic subtype 5 glutamate receptor (mGluR5) plays a critical role in synaptic plasticity besides its involvement in numerous neurological disorders, such as depression. As mGluR5 availability in humans is altered in sleep deprivation, we hypothesized that mGluR5 availability underlies a circadian variation. To investigate whether mGluR5 underlies potential circadian changes we measured its density in a randomized fashion at six different daytimes in 11 adult Sprague-Dawley rats.

Relapse patterns after radiochemotherapy of glioblastoma with FET PET-guided boost irradiation and simulation to optimize radiation target volume.

Background: O-(2-18 F-fluoroethyl)-L-tyrosine-(FET)-PET may be helpful to improve the definition of radiation target volumes in glioblastomas compared with MRI. We analyzed the relapse patterns in FET-PET after a FET- and MRI-based integrated-boost intensity-modulated radiotherapy (IMRT) of glioblastomas to perform an optimized target volume definition.

Methods: A relapse pattern analysis was performed in 13 glioblastoma patients treated with radiochemotherapy within a prospective phase-II-study between 2008 and 2009.