Radiolabelling and preclinical characterization of Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa.

Purpose: Τhis study aimed to optimize the Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of Zr-Df-bintrafusp alfa and Zr-Df-control radioconjugates.

Methods: Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-β receptor II (TGF-βRII), avelumab (anti-PD-L1 human IgG1 control antibody), isotype control (mutated inactive anti-PD-L1 IgG1 control antibody), and trap control (mutated inactive anti-PD-L1 human IgG1 fused to active TGF-βRII) were chelated with p-isothiocyanatobenzyl-desferrioxamine (Df). After radiolabelling with zirconium-89 (Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro.

Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer.

Introduction: Altered lipid metabolism and subsequent changes in cellular lipid composition have been observed in prostate cancer cells, are associated with poor clinical outcome, and are promising targets for metabolic therapies. This study reports for the first time on the synthesis of a phospholipid radiotracer based on the phospholipid 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (PC44:12) to allow tracking of polyunsaturated lipid tumor uptake via PET imaging. This tracer may aid in the development of strategies to modulate response to therapies targeting lipid metabolism in prostate cancer.

Automated synthesis of F radiolabelled indole containing Oncrasin-like molecules; a comparison of iodonium salts and boronic ester chemistry.

Background: Oncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. We aimed to develop a radiolabelled form of Oncrasin-1 to enable in-vivo imaging of mutant KRAS expression in malignant tumours. This work outlines the synthesis of 3 fluorinated derivatives and development of iodonium salt and boronic ester precursors for radiolabelling with the F isotope.

Synthesis and validation of [F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone.

Background: Targeted therapy of HER2 positive breast cancer has led to clinical success in some cases with primary and secondary resistance being major obstacles. Due to the substantial involvement of mTOR kinase in cell growth and proliferation pathways it is now targeted in combination treatments to counteract HER2 targeted therapy resistance. However, the selection of receptive patient populations for a specific drug combination is crucial.

Molecular imaging of T cell co-regulator factor B7-H3 with Zr-DS-5573a.

B7-H3 is a transmembrane protein widely expressed in a variety of cancers and has been shown to play a role in anti-tumor immunity. This study aims to develop a molecular imaging probe to identify B7-H3 expression in tumors and to develop Zr-DS-5573a as a theranostic that could aid patient selection in clinical Phase I studies. The anti-B7-H3 humanised monoclonal antibody DS-5573a was labeled with zirconium-89 (Zr-), and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen binding affinity (Scatchard analysis), and serum stability .

Improved synthesis of [(18)F]FLETT via a fully automated vacuum distillation method for [(18)F]2-fluoroethyl azide purification.

The synthesis of [(18)F]2-fluoroethyl azide and its subsequent click reaction with 5-ethynyl-2'-deoxyuridine (EDU) to form [(18)F]FLETT was performed using an iPhase FlexLab module. The implementation of a vacuum distillation method afforded [(18)F]2-fluoroethyl azide in 87±5.3% radiochemical yield.

Fully automated synthesis and coupling of [(18) F]FBEM to glutathione using the iPHASE FlexLab module.

Site-specific radiolabelling of peptides or antibodies using [(18) F]FBEM is often preferred over non-site-specific radiolabelling with [(18) F]SFB because it does not affect the affinity of the antibody to its target. Unfortunately, the synthesis of [(18) F]FBEM and its conjugation to thiol containing macromolecules requires some manual intervention, which leads to radiation exposure of the radiochemist. In this publication, we report on the complete automation of [(18) F]FBEM production and its subsequent conjugation to glutathione using a slightly modified iPHASE FlexLab module.

Structural studies on cycloadducts of furan, 2-methoxyfuran, and 5-trimethylsilylcyclopentadiene with maleic anhydride and N-methylmaleimide.

The early stages of the retro-Diels-Alder reaction are clearly apparent in the structures of the cycloadducts formed between furan or 5-trimethylsilylcyclopentadiene with maleic anhydride and N-methylmaleimide. The degree of lengthening of the C-C bonds that break in this reaction is clearly related to the known reactivity of these cycloadducts toward this reaction. In the structures of the cycloadducts 21 and 22 derived from 2-methoxyfuran, the early stages of an alternative fragmentation reaction are apparent, consistent with the reactivity of these compounds in solution.

Structures of oxygenated cyclohexa-1,3-diene-maleic anyhydride cycloadducts. Structural evidence suggests a stepwise retro-Diels-Alder reaction.

The structures of a series of cyclohexadiene-maleic anhydride cycloadducts show structural parameters consistent with the early stages of the retro-Diels-Alder (rDA) reaction in the ground state structure. The symmetrical adduct shows effects consistent with a synchronous rDA reaction. An asynchronous rDA reaction is suggested in the structure of 8, and the first evidence suggesting a two-step retro-Diels-Alder mechanism is provided by the deoxygenated adduct 9.

Manifestations of the Alder-Rickert reaction in the structures of bicyclo[2.2.2]octadiene and bicyclo[2.2.2]octene derivatives.

The Alder-Rickert ethylene extrusion reaction manifests in the ground state structures of compounds 9-12 which contain the bicyclo[2.2.2]octadiene moiety and compounds 13, 14, and 17-20 which contain the bicyclo[2.