Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain.

The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD.

Poly(ADP-ribose) polymerase (PARP)-targeted PET imaging in non-oncology application: a pilot study in preclinical models of nonalcoholic steatohepatitis.

Poly(ADP-ribose) polymerase (PARP) activation often indicates a disruptive signal to lipid metabolism, the physiological alteration of which may be implicated in the development of non-alcoholic fatty liver disease. The objective of this study was to evaluate the capability of [Ga]DOTA-PARPi PET to detect hepatic PARP expression in a non-alcoholic steatohepatitis (NASH) mouse model. In this study, male C57BL/6 mice were subjected to a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for a 12-week period to establish preclinical NASH models.

Radiochemistry for positron emission tomography.

Positron emission tomography (PET) constitutes a functional imaging technique that is harnessed to probe biological processes in vivo. PET imaging has been used to diagnose and monitor the progression of diseases, as well as to facilitate drug development efforts at both preclinical and clinical stages. The wide applications and rapid development of PET have ultimately led to an increasing demand for new methods in radiochemistry, with the aim to expand the scope of synthons amenable for radiolabeling.

Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M PET ligand that allows the non-invasive visualization of M in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound a subtype-selective positive allosteric modulator (PAM).

Optimization and Evaluation of AlF Labeling Using a NOTA-or RESCA1-Conjugated AE105 Peptide Antagonist of uPAR.

Fluorine-18 displays almost ideal decay properties for positron emission tomography (PET) and allows for large scale production. As such, simplified methods to radiolabel peptides with fluorine-18 are highly warranted. Chelation of aluminium fluoride-18 toward specific peptides represents one method to achieve this.

[Hyperlactataemia].

It is a common but flawed presumption that blood lactate reflects the lactic acid production in the body's tissues. Lactate is formed directly from pyruvate and functions to dampen reductions in intracellular pH through lactate-H+ cotransport to the extracellular space. Though this may give rise to elevated blood lactate, increased lactate production is not the cause of metabolic acidosis in such instances.

Evaluation of [Cu]Cu-NOTA-PEG-H-Tz for Pretargeted Imaging in LS174T Xenografts-Comparison to [In]In-DOTA-PEG-BisPy-Tz.

Pretargeted nuclear imaging for the diagnosis of various cancers is an emerging and fast developing field. The tetrazine ligation is currently considered the most promising reaction in this respect. Monoclonal antibodies are often the preferred choice as pretargeting vector due to their outstanding targeting properties.

Fluorine-18 labeled aldehydes as prosthetic groups for oxime coupling with a FVIIa protein.

New F-labeled nonvolatile aldehyde prosthetic groups derived from [ F]F-Py-TFP and spirocyclic iodonium (III)ylide precursors for late stage F-labeling were developed. These precursors were characterized, F-labeled, and compared in reactivity for oxime coupling. Oxime coupling was performed on an amino-oxy modified inhibited factor VII (FVIIai-ONH ) in low concentration to prove the applicability of the proposed method.

Affinity-Guided Conjugation to Antibodies for Use in Positron Emission Tomography.

The radionuclide copper-64 is widely used in combination with biomolecules, such as antibodies, for positron emission tomography (PET). Copper-64 is ideal for the imaging of biomolecules with long circulation times due to its relatively long half-life, and when conjugated to an antibody, specific cells can be targeted in vivo. Here, we have prepared a trastuzumab-chelator conjugate by using affinity-guided conjugation, in which an azide was attached to the antibody prior to a strain promoted azide-alkyne cycloaddition reaction with DBCO-PEG-NOTA.

Oxime Coupling of Active Site Inhibited Factor Seven with a Nonvolatile, Water-Soluble Fluorine-18 Labeled Aldehyde.

A nonvolatile fluorine-18 aldehyde prosthetic group was developed from [F]SFB, and used for site-specific labeling of active site inhibited factor VII (FVIIai). FVIIai has a high affinity for tissue factor (TF), a transmembrane protein involved in angiogenesis, proliferation, cell migration, and survival of cancer cells. A hydroxylamine N-glycan modified FVIIai (FVIIai-ONH) was used for oxime coupling with the aldehyde [F]2 under mild and optimized conditions in an isolated RCY of 4.

Site-Specific Cu Labeling of the Serine Protease, Active Site Inhibited Factor Seven Azide (FVIIai-N), Using Copper Free Click Chemistry.

A method for site-specific radiolabeling of the serine protease active site inhibited factor seven (FVIIai) with Cu has been applied using a biorthogonal click reaction. FVIIai binds to tissue factor (TF), a trans-membrane protein involved in hemostasis, angiogenesis, proliferation, cell migration, and survival of cancer cells. First a single azide moiety was introduced in the active site of this 50 kDa protease.

PET Imaging of Tissue Factor in Pancreatic Cancer Using 64Cu-Labeled Active Site-Inhibited Factor VII.

Unlabelled: Tissue factor (TF) is the main initiator of the extrinsic coagulation cascade. However, TF also plays an important role in cancer. TF expression has been reported in 53%-89% of all pancreatic adenocarcinomas, and the expression level of TF has in clinical studies correlated with advanced stage, increased microvessel density, metastasis, and poor overall survival.

Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site-Inhibited Factor VII.

Unlabelled: Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF.

Synthesis and characterization of (18)F-labeled active site inhibited factor VII (ASIS).

Activated factor VII blocked in the active site with Phe-Phe-Arg-chloromethyl ketone (active site inhibited factor VII (ASIS)) is a 50-kDa protein that binds with high affinity to its receptor, tissue factor (TF). TF is a transmembrane glycoprotein that plays an important role in, for example, thrombosis, metastasis, tumor growth, and tumor angiogenesis. The aim of this study was to develop an (18)F-labeled ASIS derivative to assess TF expression in tumors.