Synthesis and preclinical evaluation of a selective MET kinase positron emission tomography tracer.

The tyrosine kinase MET (hepatocyte growth factor receptor) is activated or mutated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (1) formed the basis for a bioisosteric replacement, leading to the deoxyfluorinated analog [ F]2.

A new automated and putatively versatile synthesis of the PSMA-ligand derivative [F]DCFPyL using the FASTlab synthesizer.

Background: Noninvasive molecular imaging using peptides and biomolecules labelled with positron emitters has become important for detection of cancer and other diseases with PET (positron emission tomography). The positron emitting radionuclide fluorine-18 is widely available in high yield from cyclotrons and has favorable decay (t 109.7 min) and imaging properties.

Preclinical evaluation of [F]cabozantinib as a PET imaging agent in a prostate cancer mouse model.

Introduction: Cabozantinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma, and is currently in clinical trials for the treatment of prostate cancer and others. It exerts its therapeutic effect mainly through inhibition of the tyrosine kinases MET (hepatocyte growth factor receptor) and VEGFR2 (vascular endothelial growth factor receptor 2), in addition to several other kinases involved in cancer. PET imaging with TKIs such as [F]cabozantinib could potentially aid in cancer diagnosis and guide treatment.

Fluorine-18-Labeled Antibody Ligands for PET Imaging of Amyloid-β in Brain.

Antibodies are attractive as radioligands due to their outstanding specificity and high affinity, but their inability to cross the blood-brain barrier (BBB) limits their use for CNS targets. To enhance brain distribution, amyloid-β (Aβ) antibodies were fused to a transferrin receptor (TfR) antibody fragment, enabling receptor mediated transport across the BBB. The aim of this study was to label these bispecific antibodies with fluorine-18 and use them for Aβ PET imaging.

Correction: Towards dual inhibitors of the MET kinase and WNT signaling pathway; design, synthesis and biological evaluation.

[This corrects the article DOI: 10.1039/C9RA08954C.].

A Survey of Molecular Imaging of Opioid Receptors.

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as μ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although -[methyl-C]morphine, -codeine and -heroin did not show significant binding . [C]Diprenorphine ([C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the μ-preferring agonist [C]carfentanil ([C]Caf).

Towards dual inhibitors of the MET kinase and WNT signaling pathway; design, synthesis and biological evaluation.

Both the kinase MET and the WNT signaling pathway are attractive targets in cancer therapy, and synergistic effects have previously been observed in animal models upon simultaneous inhibition. A strategy towards a designed multiple ligand of MET and WNT signaling is pursued based on the two hetero biaryl systems present in both the MET inhibitor tepotinib and WNT signaling inhibitor TC-E 5001. Initial screening was conducted to find the most suitable ring systems for further optimization, whereas a second screen explored modifications towards pyridazinones and triazolo pyridazines.

Improved Drug Delivery to Brain Metastases by Peptide-Mediated Permeabilization of the Blood-Brain Barrier.

Patients with melanoma have a high risk of developing brain metastasis, which is associated with a dismal prognosis. During early stages of metastasis development, the blood-brain barrier (BBB) is likely intact, which inhibits sufficient drug delivery into the metastatic lesions. We investigated the ability of the peptide, K16ApoE, to permeabilize the BBB for improved treatment with targeted therapies preclinically.

Design, synthesis and biological evaluation of 6-substituted quinolines derived from cabozantinib as c-Met inhibitors.

Based on the cabozantinib scaffold, novel c-Met inhibitors were rationalized from the limited knowledge of structure-activity relationships for the quinoline 6-position. Emphasis was given to modifications capable of engaging in additional polar interactions with the c-Met active site. In addition, ortho-fluorinations of the terminal benzene ring were explored.

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.

One-step synthesis of [ F]cabozantinib for use in positron emission tomography imaging of c-Met.

Cabozantinib is an FDA-approved kinase inhibitor for the treatment of medullary thyroid cancer and advanced renal cell carcinoma, which exerts its therapeutic effect by inhibiting, among others, the tyrosine kinase c-Met. Noninvasive imaging techniques are becoming increasingly important clinically to ensure drug efficacy, staging, monitoring, and patient stratification. PET isotope labelled tyrosine kinase inhibitors have, for the same reason, potential as PET tracers for imaging of various cancers.

Crystal structure of 6,7-dimeth-oxy-1-(4-nitro-phen-yl)quinolin-4(1)-one: a mol-ecular scaffold for potential tubulin polymerization inhibitors.

The protein tubulin is central for maintaining normal cellular processes, and mol-ecules inter-fering with the tubulin dynamics have potential in the treatment of cancerous diseases. The title compound, CHNO, was prepared as a lead compound in a project dedicated to the development of therapeutic agents binding to the colchicine binding site on tubulin, thereby inter-fering with the cell division in cancer cells. It holds many of the main structural characteristics for colchicine binding and has the potential for further modification and functionalization.

Brain penetrant small molecule (18)F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats.

Introduction: The gonadotropin releasing hormone receptor (GnRH-R) has a well-described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood-brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography.

Synthesis and in vitro evaluation of small-molecule [18F] labeled gonadotropin-releasing hormone (GnRH) receptor antagonists as potential PET imaging agents for GnRH receptor expression.

Two novel small molecule gonadotropin-releasing hormone (GnRH) receptor antagonists (12 and 13) of the furamide-class were synthesized and evaluated in vitro for their receptor binding affinities for the rat GnRH receptor. Radiolabeling with no carrier added fluorine-18 of the appropriate precursors was investigated in a one-step reaction. LogP (Octanol/PBS pH 7.

Standardization of fluorine-18 manufacturing processes: new scientific challenges for PET.

In [(18)F]fluoride chemistry, the minute amounts of radioactivity taking part in a radiolabeling reaction are easily outnumbered by other reactants. Surface areas become comparably larger and more influential than in standard fluorine chemistry, while leachables, extractables, and other components that normally are considered small impurities can have a considerable influence on the efficiency of the reaction. A number of techniques exist to give sufficient (18)F-tracer for a study in a pre-clinical or clinical system, but the chemical and pharmaceutical understanding has significant gaps when it comes to scaling up or making the reaction more efficient.

Radiosynthesis and biodistribution of a prosthetic group (¹⁸F-FENMA) conjugated to cyclic RGD peptides.

We have recently reported a new N-methylaminooxy-based prosthetic group for the site-selective introduction of ¹⁸F-fluorine under mild acidic aqueous conditions into model peptides functionalized with a Michael acceptor moiety. To further investigate the utility of this methodology, the radiosynthesis of two cyclic RGD peptides was carried out, and in vivo biodistribution and microPET studies were performed in tumor-bearing mice. A cyclic RGD peptide was functionalized with the Michael acceptors trans-β-nitrostyrene carboxylic acid and 3-vinylsulfonylpropionic acid.

One step radiosynthesis of 6-[(18)F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester ([(18)F]F-Py-TFP): a new prosthetic group for efficient labeling of biomolecules with fluorine-18.

The labeling of biomolecules for positron emission tomography (PET) with no-carrier-added fluorine-18 is almost exclusively accomplished using prosthetic groups in a two step procedure. The inherent complexity of the process renders full automation a challenge and leads to protracted synthesis times. Here we describe a new (18)F-labeled prosthetic group based on nicotinic acid tetrafluorophenyl ester.

Didanosine ester prodrugs: synthesis, albumin binding properties and pharmacokinetic studies in rats.

Three half-ester derivatives 10-12 of 5'-O-2',3'-dideoxydidanosine (DDI, 1) have been synthesized. The compounds exhibited excellent correlation between partition coefficients LogP and relative in vitro bovine serum albumin binding. Using high-performance liquid chromatography-mass spectrometry (LC-MS), DDI (1) was quantitatively determined in rat plasma after intravenous injection of the azelaic acid monoester derivative (11) of DDI.

A novel prosthetic group for site-selective labeling of peptides for positron emission tomography.

Efficient methodologies for the radiolabeling of peptides with [(18)F]fluoride are a prerequisite to enabling commercialization of peptide-containing radiotracers for positron emission tomography (PET) imaging. It was the purpose of this study to investigate a novel chemoselective ligation reaction comprising conjugation of an [(18)F]-N-methylaminooxy-containing prosthetic group to a functionalized peptide. Twelve derivatives of general formula R1-CO-NH-Lys-Gly-Phe-Gly-Lys-OH were synthesized where R1 was selected from a short list of moieties anticipated to be reactive toward the N-methylaminooxy group.