PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator.

Stimulation of the M muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e.

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the Fragile X Mental Retardation (FMR1) gene. The resulting loss of Fragile X Mental Retardation Protein (FMRP) leads to excessive glutamate signaling via metabotropic glutamate subtype 5 receptors (mGluR5) which has been implicated in the pathogenesis of the disorder. In the present study we used the radioligand 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB) in simultaneous PET-MR imaging of males with FXS and age- and gender-matched controls to assess the availability of mGlu5 receptors in relevant brain areas.

In vivo quantitative mapping of human mitochondrial cardiac membrane potential: a feasibility study.

Purpose: Alteration in mitochondrial membrane potential (ΔΨ) is an important feature of many pathologic processes, including heart failure, cardiotoxicity, ventricular arrhythmia, and myocardial hypertrophy. We present the first in vivo, non-invasive, assessment of regional ΔΨ in the myocardium of normal human subjects.

Methods: Thirteen healthy subjects were imaged using [F]-triphenylphosphonium ([F]TPP+) on a PET/MR scanner.

Development, validation and regulatory acceptance of improved purification and simplified quality control of [N] Ammonia.

Background: [N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time.

Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [F]MK6240 in human subjects.

Purpose: [F]MK6240 was developed for PET imaging of tau aggregates, which are implicated in Alzheimer's disease. The goal of this work was to evaluate the kinetics of [F]MK6240 and to investigate different strategies for in-vivo quantification of tau aggregates in humans.

Methods: Thirty-five subjects, consisting of 18 healthy controls (CTRL), 11 subjects with mild cognitive impairment (MCI) and six with Alzheimer's Disease (AD), underwent dynamic [F]MK6240 PET scans.

cGMP production of the radiopharmaceutical [ F]MK-6240 for PET imaging of human neurofibrillary tangles.

Fluorine-18-labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([ F]MK-6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2-step radiosynthesis of [ F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FX . Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [ F]fluoride (K[ F]/K ) was performed by conventional heating, followed by acid deprotection and semipreparative high-performance liquid chromatography under isocratic conditions.

A report of the automated radiosynthesis of the tau positron emission tomography radiopharmaceutical, [ F]-THK-5351.

The radiotracer, [ F]-THK-5351, is a highly selective and high-binding affinity PET imaging agent for aggregates of hyper-phosphorylated tau protein. Our report is a simplified 1-pot, 2-step radiosynthesis of [ F]-THK-5351. This report is broadly applicable for routine clinical production and multi-center trials on account of favorable half-life of flourine-18 and the use of a commercially available radiosynthesis module, the GE TRACERlab™ FX .

Pharmacokinetic Evaluation of the Tau PET Radiotracer F-T807 (F-AV-1451) in Human Subjects.

F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of F-T807 with arterial blood sampling.

Tau positron emission tomographic imaging in aging and early Alzheimer disease.

Objective: Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies.

Methods: We acquired tau positron emission tomography (PET) using (18)F T807 (AV1451), and amyloid-β PET using (11)C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia.

Results: We found abnormally high cortical (18)F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls.

Iodonium ylide-mediated radiofluorination of 18F-FPEB and validation for human use.

Unlabelled: Translation of new methodologies for labeling nonactivated aromatic molecules with (18)F remains a challenge. Here, we report a one-step, regioselective, metal-free (18)F-labeling method that uses a hypervalent iodonium(III) ylide precursor, to prepare the radiopharmaceutical (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB).

Methods: Automated radiosynthesis of (18)F-FPEB was achieved by reaction of the ylide precursor (4 mg) with (18)F-Et4NF in dimethylformamide at 80°C for 5 min and formulated for injection within 1 h.

Microfluidic continuous-flow radiosynthesis of [F]FPEB suitable for human PET imaging.

The synthesis of fluorine-18 labeled 3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([F]FPEB) for imaging metabotropic glutamate receptor subtype type 5 (mGluR5) was achieved with a commercial continuous-flow microfluidics device. This work represents the first positron emission tomography (PET) radiopharmaceutical that is suitable for human use with this technology. We also describe a validated synthesis of [F]FPEB with a commercial reactor-based system.

First human use of a radiopharmaceutical prepared by continuous-flow microfluidic radiofluorination: proof of concept with the tau imaging agent [18F]T807.

Despite extensive preclinical imaging with radiotracers developed by continuous-flow microfluidics, a positron emission tomographic (PET) radiopharmaceutical has not been reported for human imaging studies by this technology. The goal of this study was to validate the synthesis of the tau radiopharmaceutical 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([18F]T807) and perform first-in-human PET scanning enabled by microfluidic flow chemistry. [18F]T807 was synthesized by our modified one-step method and adapted to suit a commercial microfluidic flow chemistry module.

A concise radiosynthesis of the tau radiopharmaceutical, [(18) F]T807.

Fluorine-18 labeled 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([(18) F]T807) is a potent and selective agent for imaging paired helical filaments of tau and is among the most promising PET radiopharmaceuticals for this target in early clinical trials. The present study reports a simplified one-step method for the synthesis of [(18) F]T807 that is broadly applicable for routine clinical production using a GE TRACERlab™ FXFN radiosynthesis module. Key facets of our optimized radiosynthesis include development and use of a more soluble protected precursor, tert-butyl 7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate, as well as new HPLC separation conditions that enable a facile one-step synthesis.

Free somatostatin receptor fraction predicts the antiproliferative effect of octreotide in a neuroendocrine tumor model: implications for dose optimization.

Somatostatin receptors (SSTR) are highly expressed in well-differentiated neuroendocrine tumors (NET). Octreotide, an SSTR agonist, has been used to suppress the production of vasoactive hormones and relieve symptoms of hormone hypersecretion with functional NETs. In a clinical trial, an empiric dose of octreotide treatment prolonged time to tumor progression in patients with small bowel neuroendocrine (carcinoid) tumors, irrespective of symptom status.

A container closure system that allows for greater recovery of radiolabeled peptide compared to the standard borosilicate glass system.

Objectives: Often peptides used in synthesis of radiopharmaceutical PET tracers are lipophilic and adhere to the walls of container closure systems (CCS) such that costly peptide and product are not fully recoverable after synthesis occurs. This investigation compares a standard United States Pharmacopeia (USP) Type I borosilicate glass CCS to a cyclic polyolefin copolymer Crystal Zenith(®) (CZ) CCS, for (68)Ga-chloride and (68)Ga-DOTATOC ([(68)Ga] Ga-DOTA-D-Phe1-Tyr3-octreotide) retention in the reaction vial after labeling.

Methods: (68)Gallium labeling of DOTATOC was conducted by adding (68)Ga-chloride, 2M HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid) or 0.

Microfluidic single vessel production of hypoxia tracer 1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole ([18F]-FMISO).

We report an automated synthesis of [(18)F]-FMISO utilizing a prototype microfluidic radiochemistry module. The instrument allows for production of the tracer with 58%±2% (11 runs) decay corrected yield. Total time of production, including synthesis and purification averages 60 min.