Preliminary PET imaging of [C]evobrutinib in mouse models of colorectal cancer, SARS-CoV-2, and lung damage: Radiosynthesis via base-aided palladium-NiXantphos-mediated C-carbonylation.

Evobrutinib is a second-generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and lipopolysaccharide (LPS)-induced lung damage. Herein, we report the automated radiosynthesis of [C]evobrutinib using a base-aided palladium-NiXantphos-mediated C-carbonylation reaction.

Relative Biological Effectiveness (RBE) of [Cu]Cu and [Lu]Lu-NOTA-panitumumab F (ab') radioimmunotherapeutic agents vs. γ-radiation for decreasing the clonogenic survival in vitro of human pancreatic ductal adenocarcinoma (PDAC) cells.

Introduction: Our objective was to compare [Cu]Cu-NOTA-panitumumab F(ab') and [Lu]Lu-NOTA-panitumumab F(ab') radioimmunotherapy (RIT) agents for decreasing the clonogenic survival fraction (SF) in vitro of EGFR-positive human pancreatic ductal adenocarcinoma (PDAC) cell lines and estimate the relative biological effectiveness (RBE) vs. γ-radiation (XRT).

Methods: EGFR-positive PDAC cell lines (AsPC-1, PANC-1, MIAPaCa-2, Capan-1) and EGFR-knockout PANC-1 EGFR KO cells were treated in vitro for 18 h with (0-19.

PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[F]fluoro-6-deoxy-D-fructose.

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[F]FDF will specifically image microglia following neuroinflammatory insult. 6-[F]FDF and, for comparison, [F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo.

PET imaging of glycogen synthase kinase-3 in pancreatic cancer xenograft mouse models.

Glycogen synthase kinase-3 (GSK-3) contributes to tumorigenesis in pancreatic cancer by modulating cell proliferation and survival. This study evaluated the lead GSK-3 targeted PET radiotracers for neuro-PET imaging, [C]PF-367 and [C]OCM-44, in pancreatic cancer xenograft mice. Immunohistochemistry showed that GSK-3α and GSK-3β were overexpressed in PANC-1 xenografts.

Repurposing [C]MC1 for PET Imaging of Cyclooxygenase-2 in Colorectal Cancer Xenograft Mouse Models.

Purpose: Cyclooxygenase-2 (COX-2) is a target for inflammation and colorectal cancer (CRC). This study evaluated the COX-2 neuro-PET radiopharmaceutical, [C]MC1, in CRC xenograft mice.

Procedures: [C]MC1 was evaluated in ICRscid mice with HT-29 and HCT-116 CRC xenografts, with high and low COX-2 expression, respectively, by immunohistochemistry, cellular uptake, dynamic PET/MR imaging, ex vivo biodistribution, and radiometabolite analysis.

Radiosynthesis of [C]Ibrutinib Pd-Mediated [C]CO Carbonylation: Preliminary PET Imaging in Experimental Autoimmune Encephalomyelitis Mice.

Ibrutinib is a first-generation Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in autoimmune diseases and has consequently been developed as a positron emission tomography (PET) radiotracer. Herein, we report the automated radiosynthesis of [C]ibrutinib through C-carbonylation of the acrylamide functional group, by reaction of the secondary amine precursor with [C]CO, iodoethylene, and palladium-NiXantphos. [C]Ibrutinib was reliably formulated in radiochemical yields of 5.

Artificial intelligence for molecular neuroimaging.

In recent years, artificial intelligence (AI) or the study of how computers and machines can gain intelligence, has been increasingly applied to problems in medical imaging, and in particular to molecular imaging of the central nervous system. Many AI innovations in medical imaging include improving image quality, segmentation, and automating classification of disease. These advances have led to an increased availability of supportive AI tools to assist physicians in interpreting images and making decisions affecting patient care.

Repurposing C-PS13 for PET Imaging of Cyclooxygenase-1 in Ovarian Cancer Xenograft Mouse Models.

Cyclooxygenase-1 (COX-1), a biomarker for neuroinflammation, is implicated in the progression and prognosis of ovarian cancer (OvCa). This study considered the repurposing of C-labeled 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1-1,2,4-triazole (C-PS13), a COX-1 PET neuroimaging radiopharmaceutical, in OvCa xenograft mouse models. C-PS13 was evaluated in ICRscid mice with subcutaneous or intraperitoneal human OVCAR-3 OvCa xenografts by dynamic PET/MRI, ex vivo biodistribution, and radiometabolite analysis of plasma and tumor.

Radioimmunotherapy of human pancreatic cancer xenografts in NOD-scid mice with [Cu]Cu-NOTA-panitumumab F(ab') alone or combined with radiosensitizing gemcitabine and the PARP inhibitor, rucaparib.

Introduction: Our objective was to determine the feasibility of extending our previously reported PET imaging study of pancreatic cancer (PnCa) with [Cu]Cu-NOTA-panitumumab F(ab') to radioimmunotherapy (RIT) by exploiting the β-particle and Auger electron emissions of Cu (PET theranostic concept). To enhance the effectiveness of [Cu]Cu-NOTA-panitumumab F(ab'), we further combined RIT with radiosensitizing gemcitabine (GEM) and the poly(ADP)ribose polymerase inhibitor (PARPi), rucaparib.

Methods: Normal tissue toxicity was assessed in non-tumor-bearing NOD-scid mice injected i.

Improving PET Imaging Acquisition and Analysis With Machine Learning: A Narrative Review With Focus on Alzheimer's Disease and Oncology.

Machine learning (ML) algorithms have found increasing utility in the medical imaging field and numerous applications in the analysis of digital biomarkers within positron emission tomography (PET) imaging have emerged. Interest in the use of artificial intelligence in PET imaging for the study of neurodegenerative diseases and oncology stems from the potential for such techniques to streamline decision support for physicians providing early and accurate diagnosis and allowing personalized treatment regimens. In this review, the use of ML to improve PET image acquisition and reconstruction is presented, along with an overview of its applications in the analysis of PET images for the study of Alzheimer's disease and oncology.

EGFR-Targeted Metal Chelating Polymers (MCPs) Harboring Multiple Pendant PEG Chains for MicroPET/CT Imaging of Patient-Derived Pancreatic Cancer Xenografts.

In this study, we developed a new generation of metal chelating polymer (MCP) reagents that carry multiple polyethylene glycol (PEG) pendant groups to provide stealth to MCP-based radioimmunoconjugates (RICs). We describe the MCP synthesis for covalent attachment to panitumumab F(ab') fragments (pmabF(ab')) in which different numbers of pendant methoxy-PEG chains [M = 2000, ∼45 ethylene glycol (EG) repeat units, referred to as PEG] are incorporated into the polymer backbone. The pendant PEG chains were designed to provide a protein-repellant corona so that metal chelators attached closer to the polymer backbone will be less apparent to the physiological environment.

Radioimmunotherapy of cancer with high linear energy transfer (LET) radiation delivered by radionuclides emitting α-particles or Auger electrons.

Radioimmunotherapy (RIT) aims to selectively deliver radionuclides emitting α-particles, β-particles or Auger electrons to tumors by conjugation to monoclonal antibodies (mAbs) that recognize tumor-associated antigens/receptors. The approach has been most successful for treatment of non-Hodgkin's B-cell lymphoma but challenges have been encountered in extending these promising results to the treatment of solid malignancies. These challenges include the low potency of β-particle emitters such as I, Lu or Y which have been commonly conjugated to the mAbs, due to their low linear energy transfer (LET=0.

Metal-Chelating Polymers (MCPs) with Zwitterionic Pendant Groups Complexed to Trastuzumab Exhibit Decreased Liver Accumulation Compared to Polyanionic MCP Immunoconjugates.

Metal-chelating polymers (MCPs) can amplify the radioactivity delivered to cancer cells by monoclonal antibodies or their Fab fragments. We focus on trastuzumab (tmAb), which is used to target cancer cells that overexpress human epidermal growth factor receptor 2 (HER2). We report the synthesis and characterization of a biotin (Bi) end-capped MCP, Bi-PAm(DET-DTPA)36, a polyacrylamide with diethylenetriaminepentaacetic acid (DTPA) groups attached as monoamides to the polymer backbone by diethylenetriamine (DET) pendant groups.

Trastuzumab Labeled to High Specific Activity with (111)In by Site-Specific Conjugation to a Metal-Chelating Polymer Exhibits Amplified Auger Electron-Mediated Cytotoxicity on HER2-Positive Breast Cancer Cells.

Our objective was to evaluate the cytotoxicity toward HER2-positive human breast cancer (BC) cells of trastuzumab modified site-specifically with a metal-chelating polymer (MCP) that presents multiple DTPA chelators for complexing (111)In. (111)In emits subcellular range Auger electrons that induce multiple lethal DNA double-strand breaks (DSBs) in cells. MCPs were synthesized with a polyglutamide backbone with 24 or 29 pendant DTPA groups, with or without nuclear translocation sequence (NLS) peptide modification and a terminal hydrazide group for reaction with aldehydes generated by sodium periodate (NaIO4)-oxidation of glycans on the Fc-domain of trastuzumab.

MicroPET/CT imaging of patient-derived pancreatic cancer xenografts implanted subcutaneously or orthotopically in NOD-scid mice using (64)Cu-NOTA-panitumumab F(ab')2 fragments.

Introduction: Our objective was to study microPET/CT imaging of patient-derived pancreatic cancer xenografts in NOD-scid mice using F(ab')2 fragments of the fully-human anti-EGFR monoclonal antibody, panitumumab (Vectibix) labeled with (64)Cu. More than 90% of pancreatic cancers are EGFR-positive.

Methods: F(ab')2 fragments were produced by proteolytic digestion of panitumumab IgG or non-specific human IgG, purified by ultrafiltration then modified with NOTA chelators for complexing (64)Cu.

Synthesis of polyglutamide-based metal-chelating polymers and their site-specific conjugation to trastuzumab for auger electron radioimmunotherapy.

Three types of metal-chelating polymers (MCPs) with hydrazide end groups were synthesized. (1) The first set of polymers (the F-series) was synthesized with a furan end group, and all of the pendant groups along the chain carried only a diethylenetriaminepentaacetic acid (DTPA) metal-chelating functionality. The hydrazide was introduced via a Diels-Alder reaction between the furan and 3,3'-N-[ε-maleimidocaproic acid] hydrazide (EMCH).

Intracellular routing in breast cancer cells of streptavidin-conjugated trastuzumab Fab fragments linked to biotinylated doxorubicin-functionalized metal chelating polymers.

We describe the synthesis of a heterotelechelic metal-chelating polymer (Bi-MCP-Dox), a polyacrylamide with a number average degree of polymerization DPn = 50 (PDI = 1.2), with biotin (Bi) and doxorubicin (Dox) as functional chain ends and diethylenetriaminepentaacetic acid (DTPA) pendant groups as the binding sites for metal ions. We compared its behavior in cell-uptake experiments with a similar polymer (Bi-MCP) without Dox.

The complete N-terminal extension of heparin cofactor II is required for maximal effectiveness as a thrombin exosite 1 ligand.

Background: Heparin cofactor II (HCII) is a circulating protease inhibitor, one which contains an N-terminal acidic extension (HCII 1-75) unique within the serpin superfamily. Deletion of HCII 1-75 greatly reduces the ability of glycosaminoglycans (GAGs) to accelerate the inhibition of thrombin, and abrogates HCII binding to thrombin exosite 1. While a minor portion of HCII 1-75 can be visualized in a crystallized HCII-thrombin S195A complex, the role of the rest of the extension is not well understood and the affinity of the HCII 1-75 interaction has not been quantitatively characterized.

The effect of metal-chelating polymers (MCPs) for 111In complexed via the streptavidin-biotin system to trastuzumab Fab fragments on tumor and normal tissue distribution in mice.

Purpose: To study the effects of backbone composition and charge of biotin-functionalized metal-chelating polymers (Bi-MCPs) for (111)In complexed to streptavidin (SAv)-trastuzumab Fab fragments on tumor and normal tissue localization.

Methods: Bi-MCPs were synthesized with a polyacrylamide [Bi-PAm(DTPA)(40)], polyaspartamide [Bi-PAsp(DTPA)(33)] or polyglutamide [Bi-PGlu(DTPA)(28)] backbone and harboured diethylenetriaminepentaacetic acid (DTPA) chelators for (111)In. Bi-PAm(DTPA)(40) had a net negative charge; Bi-PAsp(DTPA)(33) and Bi-PGlu(DTPA)(28) were zwitterionic with a net neutral charge.

Biotinylated polyacrylamide-based metal-chelating polymers and their influence on antigen recognition following conjugation to a trastuzumab Fab fragment.

We report the synthesis and characterization of metal-chelating polymers (MCPs) with a terminal biotin and a polyacrylamide backbone harboring multiple diethylenetriaminepentaacetic acid (DTPA) chelating sites. These polymers are conjugated to a streptavidin (SAv)-modified Fab fragment of trastuzumab (tmFab) and subsequently complexed with (111)In through DTPA. Trastuzumab has specific targeting ability toward human epidermal growth factor receptor-2 (HER2), which is overexpressed on some types of breast cancer cells and ovarian cancer cells.