Detailed radiosynthesis of [ F]mG4P027 as a positron emission tomography radiotracer for mGluR4.

We report here the detailed radiosynthesis of [ F]mG4P027, a metabotropic glutamate receptor 4 (mGluR4) PET radiotracer, which showed superior properties to the currently reported mGluR4 radiotracers. The radiosynthesis in the automated system has been challenging, therefore we disclose here the major limiting factors for the synthesis via step-by-step examination. And we hope this thorough study will help its automation for human use in the future.

Organomediated cleavage of benzoyl group enables an efficient synthesis of 1-(6-nitropyridin-2-yl)thiourea and its application for developing F-labeled PET tracers.

A novel organomediated cleavage of benzoyl group using ethane-1,2-diamine and acetic acid under neutral condition enables an efficient synthesis of 1-(6-nitropyridin-2-yl)thiourea, which previously has been challenging to prepare by conventional methods. The successful synthesis of 1-(6-nitropyridin-2-yl)thiourea as a synthon permits development of a variety of F labeled heterocycles as PET imaging ligands such as N-(pyridin-2-yl)thiazol-2-amine derivatives. The utility of this synthon is demonstrated with the synthesis of a F-labeled PET tracer for studying prion disease.

PET imaging of mitochondrial function in acute doxorubicin-induced cardiotoxicity: a proof-of-principle study.

Mitochondrial dysfunction plays a key role in doxorubicin-induced cardiotoxicity (DIC). In this proof-of-principle study, we investigated whether PET mapping of cardiac membrane potential, an indicator of mitochondrial function, could detect an acute cardiotoxic effect of doxorubicin (DOX) in a large animal model. Eight Yucatan pigs were imaged dynamically with [F](4-Fluorophenyl)triphenylphosphonium ([F]FTPP) PET/CT.

Synthesis and Characterization of 5-(2-Fluoro-4-[C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2-pyrano[2,3-]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2-pyrano[2,3-]pyridine-7-carboxamide ([C], [C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor.

Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth.

Neurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. Unfortunately, there is no therapeutic available that treats neurodegenerative inflammation and its sequelae. Here we utilize cromolyn, a mast cell inhibitor with anti-inflammatory capabilities, and its fluorinated analogue F-cromolyn to study fibrosis-related protein regulation and secretion downstream of neuroinflammation and their ability to promote microglial phagocytosis and neurite outgrowth.

Synthesis and Characterization of [F]JNJ-46356479 as the First F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Purpose: Metabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. We have previously developed [C]7 as a PET radioligand for imaging mGluR2. Herein, [F]JNJ-46356479 ([F]8) was synthesized and characterized as the first F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.

A concise method for fully automated radiosyntheses of [F]JNJ-46356479 and [F]FITM Cu-mediated F-fluorination of organoboranes.

A modified alcohol-enhanced F-fluorodeboronation has been developed for the radiosyntheses of [F]JNJ-46356479 and [F]FITM. Unlike the [F]KF/K approach, this method tolerates the presence of sensitive heterocycles in Bpin precursors and allowing a one-step F-fluorodeboronation on the fully automated TRACERlab™ FX platform.

Improved Synthesis of the Thiophenol Precursor -(4-Chloro-3-mercaptophenyl)picolinamide for Making the mGluR4 PET Ligand.

Recently [C]mG4P012 (previously [C]KALB012 and presently named as [C]PXT012253 by Prexton Therapeutics) had been used as a biomarker during the preclinical development of a potential therapeutic drug, PXT0002331 (an mGluR4 PAM), for PD and L-dopa-induced dyskinesia. [C]mG4P012 was shown to be a promising PET radioligand for mGluR4 in the monkey brain and for further development in human subjects. However, the previously reported multi-step synthesis of the thiophenol precursor suffered from low yields and difficult workup procedures.

Synthesis and Characterization of Fluorine-18-Labeled -(4-Chloro-3-((fluoromethyl-)thio)phenyl)picolinamide for Imaging of mGluR4 in Brain.

We have synthesized and characterized [F]--(4-chloro-3-((fluoromethyl-)thio)phenyl)-picolinamide ([F]) as a potential ligand for the positron emission tomography (PET) imaging of mGluR4 in the brain. Radioligand [F] displays central nervous system drug-like properties, including mGluR4 affinity, potent mGluR4 PAM activity, and selectivity against other mGluRs, as well as sufficient metabolic stability. Radiosynthesis was carried out in two steps.

[F]Fluorocholine and [F]Fluoroacetate PET as Imaging Biomarkers to Assess Phosphatidylcholine and Mitochondrial Metabolism in Preclinical Models of TSC and LAM.

Purpose: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the or gene, characterized by neurocognitive impairment and benign tumors of the brain, skin, heart, and kidneys. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of α-smooth muscle actin-positive cells associated with cystic destruction of the lung. LAM occurs almost exclusively in women, as a TSC manifestation or a sporadic disorder ( somatic mutations).

Quantitative in vivo mapping of myocardial mitochondrial membrane potential.

Background: Mitochondrial membrane potential (ΔΨm) arises from normal function of the electron transport chain. Maintenance of ΔΨm within a narrow range is essential for mitochondrial function. Methods for in vivo measurement of ΔΨm do not exist.

Rapid computation of single PET scan rest-stress myocardial blood flow parametric images by table look up.

Purpose: We have recently reported a method for measuring rest-stress myocardial blood flow (MBF) using a single, relatively short, PET scan session. The method requires two IV tracer injections, one to initiate rest imaging and one at peak stress. We previously validated absolute flow quantitation in ml/min/cc for standard bull's eye, segmental analysis.

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.

Novel Fluorinated 8-Hydroxyquinoline Based Metal Ionophores for Exploring the Metal Hypothesis of Alzheimer's Disease.

Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer's disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo.

Pharmacodynamic imaging guides dosing of a selective estrogen receptor degrader.

Purpose: Estrogen receptor (ER) targeting is key in management of receptor-positive breast cancer. Currently, there are no methods to optimize anti-ER therapy dosing. This study assesses the use of 16α-(18)F-fluoroestradiol ((18)F-FES) PET for fulvestrant dose optimization in a preclinical ER(+) breast cancer model.

A Food and Drug Administration-approved asthma therapeutic agent impacts amyloid β in the brain in a transgenic model of Alzheimer disease.

Interfering with the assembly of Amyloid β (Aβ) peptides from monomer to oligomeric species and fibrils or promoting their clearance from the brain are targets of anti-Aβ-directed therapies in Alzheimer disease. Here we demonstrate that cromolyn sodium (disodium cromoglycate), a Food and Drug Administration-approved drug already in use for the treatment of asthma, efficiently inhibits the aggregation of Aβ monomers into higher-order oligomers and fibrils in vitro without affecting Aβ production. In vivo, the levels of soluble Aβ are decreased by over 50% after only 1 week of daily intraperitoneally administered cromolyn sodium.

Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease.

In this report, we reasoned that non-covalent modification of amyloid beta (Aβ) by crown ethers could inhibit its aggregation. We demonstrated that PiB-C, a conjugate PiB and crown ether, could significantly reduce the aggregation in vitro. Additionally, two-photon imaging showed that PiB-C could efficiently label Aβ plaques and CAAs in AD mice.

Synthesis and preclinical evaluation of [¹⁸F]FCHC for neuroimaging of fatty acid amide hydrolase.

Purpose: Fatty acid amide hydrolase (FAAH), a catabolic enzyme which regulates lipid transmitters in the endocannabinoid system, is an avidly sought therapeutic and positron emission tomography (PET) imaging target for studies involving addiction and neurological disorders. We report the synthesis of a new fluorine-18-labeled FAAH inhibitor, trans-3-(4, 5-dihydrooxazol-2-yl)phenyl-4-[(18)F]fluorocyclohexylcarbamate ([(18)F]FCHC), and its evaluation in rat brain.

Procedures: The synthesis of [(18)F]FCHC was conducted via a 3-step, 1-pot reaction, resulting in uncorrected radiochemical yields between 10 and 20% (n = 5) relative to [(18)F]fluoride, with specific activities of >5 Ci/μmol at the end of the synthesis.

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.

PET imaging of fatty acid amide hydrolase with [(18)F]DOPP in nonhuman primates.

Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [(11)C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies.

Membrane potential-dependent uptake of 18F-triphenylphosphonium--a new voltage sensor as an imaging agent for detecting burn-induced apoptosis.

Background: Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine-18 labeled phosphonium compound: (18)F-triphenylphosphonium ((18)F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis.

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.