Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated F-fluorination of boroxines, in vitro and initial in vivo evaluation.

Background: The orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed in colorectal tumors. Subtype-selective OXR PET ligands suitable for in vivo use have not yet been reported. This work reports the development of F-labeled OXR PET ligand candidates derived from the OXR antagonist suvorexant and the OX1R-selective antagonist JH112.

A protocol for controlled reactivity shift in the 2,2-difluorovinyl motif used for selective S-F and C-F bond formation.

Positron emission tomography (PET) is a powerful imaging technique for biomedical research, drug development and medical diagnosis. The power of PET lies in biochemically selective radiotracers, labelled with positron emitters like fluorine-18 image chemical processes in vivo. A rapid and remarkably efficient, unprecedented protocol to select between S-F and C-F bond formation based on activation of 1,1-difluoroethylene groups followed by selective oxidation or reduction is described.

Fully automated F-fluorination of N-succinimidyl-4-[F]fluorobenzoate ([F]SFB) for indirect labelling of nanobodies.

N-succinimidyl-4-[F]fluorobenzoate ([F]SFB), a widely used labeling agent to introduce the 4-[F]fluorobenzoyl-prosthetic group, is normally obtained in three consecutive steps from [F]fluoride ion. Here, we describe an efficient one-step labeling procedure of [F]SFB starting from a tin precursor. This method circumvents volatile radioactive side-products and simplifies automatization.

A direct fixation of CO for isotopic labelling of hydantoins using iodine-phosphine charge transfer complexes.

Herein, we report a method for the isotopic labelling of hydantoins directly from CO by means of trimethyl-λ-phosphine diiodide mediated carbonyl insertion. The method is suitable for C-labelling of diverse substrates and was implementated for C-labelling in PET-imaging facilities for the synthesis of radiotracers. Isolated yields of 90% and radiochemical yields of 89% were achieved for hydantoin containing drug candidates in formulation within 30 min with high molar activity (>400 MBq nmol).

Mild, Organo-Catalysed Borono-Deamination as a Key to Late-Stage Pharmaceutical Precursors and F-Labelled Radiotracers.

A tris(pentafluorophenyl)borane catalysed method for the synthesis of boronic acid esters from aromatic amines in yields of up to 93% was devised. Mild conditions, benign reagents, short reaction times, low temperatures and a wide substrate scope characterize the method. The reaction was found applicable to the synthesis of boronic acid ester derivatives of complex drug molecules in up to 86% isolated yield and high purity suitable for labelling.

Whole-body biodistribution and radiation dosimetry of [F]PR04.MZ: a new PET radiotracer for clinical management of patients with movement disorders.

Purpose: [F]PR04.MZ is a new PET imaging agent for dopamine transporters, providing excellent image quality and allowing for the evaluation of patients with movement disorders such as Parkinson's disease. The objective of this study was to evaluate the biodistribution and radiation dosimetry of [F]PR04.

A General Protocol for Cu-Mediated Fluoro-deamination: Sandmeyer Fluorination of Diverse Aromatic Substrates.

A Cu(I)-mediated fluoro-deamination method for nucleophilic radiofluorination was devised. The method affords fluorinated aromatic products directly from anilines under both no-carrier added and stoichiometric conditions. Isolated radiochemical yields range from 11% to 81% with high radiochemical purities and a molar activity of 58 MBq/nmol.

[18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease.

Introduction: Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter.

Pharmacological Characterization of Low-to-Moderate Affinity Opioid Receptor Agonists and Brain Imaging with F-Labeled Derivatives in Rats.

The 3,4-dichloro--(1-(dimethylamino)cyclohexyl)methyl benzamide scaffold was studied as a template for F-positron emission tomography (F-PET) radiotracer development emphasizing sensitivity to changes in opioid receptor (OR) occupancy over high affinity. Agonist potency, binding affinity, and relevant pharmacological parameters of 15 candidates were investigated. Two promising compounds and with μ-OR (MOR) selective agonist activity in the moderate range (EC = 1-100 nM) were subjected to F-fluorination, autoradiography, and small-animal PET imaging.

Discovery of a Lead Brain-Penetrating Gonadotropin-Releasing Hormone Receptor Antagonist with Saturable Binding in Brain.

We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin-releasing hormone receptor (GnRH-R) antagonists with nanomolar binding affinity. A small library of GnRH-R antagonists was synthesised in 20-67 % overall yield with the aim of identifying a high-affinity antagonist capable of crossing the blood-brain barrier. Binding affinity to rat GnRH-R was determined by autoradiography in competitive-binding studies against [ I]buserelin, and inhibition constants were calculated by using the Cheng-Prusoff equation.

Evaluation of [F]--Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies.

Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [F]-methyl lansoprazole ([F]NML). Herein we report validation of the synthesis of [F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding -difluoro enol ether precursor.

Evaluation by metabolic profiling and in vitro autoradiography of two promising GnRH-receptor ligands for brain SPECT imaging.

The increased expression of gonadotropin releasing hormone receptor (GnRH-R) in brain has been strongly linked to Alzheimer disease. Therefore, the development of radiolabeled imaging agents for GnRH-R is relevant for early diagnosis of Alzheimer disease. We have recently disclosed the discovery of two promising compounds displaying nanomolar-range affinity for the GnRH-R.

Pharmacokinetic evaluation of [F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain.

Purpose: Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [F]PR04.

Synthesis, radiosynthesis, and positron emission tomography neuroimaging using 5-[ F]fluoro-L-amino suberate.

System xc- (Sx -) has emerged as a new biological target for PET studies to detect oxidative and excitotoxic stress. Notably, applications have, thus far, been limited to tumour imaging although Sx ) may play a major role in neurodegeneration. The synthesis procedures of tosylate precursor and its translation to Sx - PET tracer 5[18F]fluoro-L-amino suberate by manual and automated radiosyntheses are described.

Synthesis and Characterization in Rodent Brain of the Subtype-Selective NR2B NMDA Receptor Ligand [C]Ro04-5595 as a Potential Radiotracer for Positron Emission Tomography.

The NR2B subunit of the -methyl-d-aspartate (NMDA) receptor has been implicated in controlling synaptic plasticity, memory, and learning. Herein, we describe an C-labeled PET radiotracer based on 1-(4-chlorophenethyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol, Ro04-5595. The radiotracer was evaluated in rats using PET.

Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates.

Genetic variation in the serotonin transporter gene () is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT).

Influx rate of F-fluoroaminosuberic acid reflects cystine/glutamate antiporter expression in tumour xenografts.

Purpose: F-fluoroaminosuberic acid (F-FASu) is a recently developed amino acid tracer for positron emission tomography (PET) of oxidative stress that may offer improved tumour assessment over the conventional tracer F-fluorodeoxyglucose (F-FDG). Our aim was to evaluate and relate dynamic F-FASu and F-FDG uptake with pharmacokinetic modelling to transporter protein expression levels in a panel of diverse tumour xenograft lines.

Methods: Four different tumour xenograft lines were implanted in female athymic nude mice: MAS98.

First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor.

Objectives: In vivo evaluations of a gonadotropin releasing hormone-receptor single photon emission computed tomography radiotracer for non-invasive detection of gonadotropin releasing homone-receptors in brain.

Results: We have used a simple, robust and high-yielding procedure to radiolabel an alpha-halogenated bioactive compound with high radiochemical yield. Literature findings showed similar alpha-halogenated compounds suitable for in vivo evaluations.

Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor.

In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4--butylphenyl)-4-piperazinyl-benzimidazole scaffold Cu-catalysed azide alkyne cycloaddition. Our main purpose was to find a more soluble compound based on the WAY207024 lead with nanomolar potency to inhibit the GnRH receptor. A late stage diversification by the use of click chemistry was, furthermore developed to allow for expansion of the library in future optimisations.

Image-Guided Development of Heterocyclic Sulfoxides as Ligands for Tau Neurofibrillary Tangles: From First-in-Man to Second-Generation Ligands.

Positron emission tomography (PET) imaging of misfolded protein aggregates that form in neurodegenerative processes of the brain is key to providing a robust marker for improved diagnosis and evaluation of treatments. We report the development of advanced radiotracer candidates based on the sulfoxide scaffold found in proton pump inhibitors (lansoprazole, prevacid) with inherent affinity to neurofibrillary tangles in Alzheimer's disease and related disorders (e.g.

Transition metal free, late-stage, regiospecific, aromatic fluorination on a preparative scale using a KF/crypt-222 complex.

We herein report the development of a convenient, regioselective, aromatic fluorination method of hypervalent iodonium ylides for synthesising fluoro-arenes on a preparative scale. This transition metal free, nucleophilic methodology provides good yields for sterically hindered substrates, irrespective of activation. The methodology simplifies reference synthesis for PET imaging.

Stereospecific radiosynthesis of 3-fluoro amino acids: access to enantiomerically pure radioligands for positron emission tomography.

A variety of substituted non-racemic aziridine-2-carboxylates equivalent to amino acids were prepared and subjected to ring opening reaction by [18F/19F]fluoride. The regio and stereospecific ring opening depends on the substituents on the nitrogen as well as both the carbons of aziridines. The applicability of the methods to afford access to 3-[18F/19F]fluoro amino acids are illustrated.

Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis and Radioligand Binding in ARC-SWE tg Mice.

We report the synthesis, radiosynthesis, and characterization of a radioligand for poly(ADP-ribose) polymerase (PARP). PARP is of central importance in cell homeostasis, neuroplasticity, and neurodegeneration in the brain. A radiolabeled PARP inhibitor was developed and used for autoradiographic quantification of PARP protein concentration in wild-type and transgenic rodent brains ex vivo in high resolution.

Recent Development of Non-Peptide GnRH Antagonists.

The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market.