Ultrafast reactivity and application in PET tracer synthesis

Humankind has always been seeking to understand biological processes within our body to diagnose and treat diseases. For a longtime, surgery was the only way to see what was going on inside a human body. That changed about a century ago with the emergence of molecular imaging, allowing us to observe processes at a molecular level, without the need for invasive procedures. Positron emission tomography (PET) is one of these techniques, which uses small molecules called tracers that are injected into the body and can be directed towards disease-specific markers. These tracers also contain a radioactive element ; this is essential as the radioactive decay of this element will emit a signal that travels through the human body and will be detected by a scanner. From the signal received by the scanner, it is possible to locate and quantify the amount of tracer present in the body and detect any abnormalities,which may possibly be indicative of a disease. Because these radioactive elements are unstable and rapidly degrade towards stable, non-radioactive elements, tracers cannot be bought or produced in advance, but instead they require on-site production. Carbon-11 and fluor-18 are two radioactive elements discussed in this thesis that can be used to make PET tracers. However,they degrade fast - within minutes to a few hours - and therefore they need to be incorporated into tracer molecules with ultrafast methods.The focus of this thesis was to discover new methodologies to incorporate the radioactive elements carbon-11 and fluor-18 into PET tracer molecules. These ultrafast reactions are not typically common in traditional synthetic chemistry, and if methods have been successfully translated to incorporate radioactive elements, the tracer molecules accessible are still restricted, creating a necessity for additional reactions

One-pot, modular approach to functionalized ketones via nucleophilic addition/Buchwald-Hartwig amination strategy

A general one-pot procedure for the 1,2-addition of organolithium reagents to amides followed by the Buchwald-Hartwig amination with in situ released lithium amides is presented. In this work amides are used as masked ketones, revealed by the addition of organolithium reagents which generates a lithium amide, suitable for subsequent Buchwald-Hartwig coupling in the presence of a palladium catalyst. This methodology allows for rapid, efficient and atom economic synthesis of aminoarylketones in good yields

Cross-coupling of [11C]methyllithium for 11C-labelled PET tracer synthesis

The cross-coupling of aryl bromides with [11C]CH3Li for the labelling of a variety of tracers for positron emission tomography (PET) is presented. The radiolabelled products were obtained in excellent yields, at rt and after short reaction times (3-5 min) compatible with the half-life of 11C (20.4 min). The automation of the protocol on a synthesis module is investigated, representing an important step towards a fast method for the synthesis of 11C-labelled compounds for PET imaging

Identificación del comportamiento caótico de las ecuaciones de Lorenz empleando máquinas de soporte vectorial

Introduction: The article is derived from the research Characterization of complex signals with Computational Intelligence techniques that has been ongoing since 2016 within the investigation Group Modelación en Ingeniería de Sistemas MIS of the Universidad Distrital Francisco José de Caldas. Objective: Determine the chaotic behavior in equations of Lorenz by using data directly taken from the time domain without prior processing, in order to classify a chaotic system. Methodology: Firstly, through simulation training data is acquired; later, it is used validation data to observe the system response. Finally, it is presented a discussion together with a set of conclusions regarding the data obtained. Results: In most of the implemented vector support machines a positive classification is prevailing. Conclusion: The data set used for the classification of the chaotic behavior in Lorenz equations was achieved implementing vector support machines, so they may be an alternative to obtaining behavior classification where data are directly taken from the time domain with none prior processing. Originality: This paper is expected to serve to further developments as in diagnosis of patients using biological signals. This work is aimed to the observation of the characteristics manifested in the vector support machines to chaotic system classification. Limitations: None preliminary data processing is performed wherefore such classification is subjected by the values obtained directly from the simulation.Introducción: el artículo se deriva de la investigación “Caracterización de señales complejas con técnicas de Inteligencia Computacional” que se encuentra en curso desde el 2016 dentro del Grupo de Investigación Modelamiento en Ingeniería de Sistemas MIS de la Universidad Distrital Francisco José de Caldas. Objetivo: identificar el comportamiento caótico que presentan las ecuaciones de Lorenz empleando datos tomados directamente en el dominio del tiempo sin procesamiento previo, para lograr clasificar un sistema caótico. Metodología: en primer lugar, se obtienen los datos de entrenamiento mediante simulación. Posteriormente, se observa la respuesta del sistema utilizando datos de validación. Finalmente, se realiza una discusión y se establecen las conclusiones en función de los datos obtenidos. Resultados: para la mayoría de las máquinas de soporte vectorial utilizadas se observa una buena clasificación. Conclusión: para el conjunto de datos empleados se logró la clasificación del comportamiento caótico de las ecuaciones de Lorenz mediante máquinas de soporte vectorial, de tal forma que estas pueden ser una alternativa para realizar la clasificación de comportamientos, donde se toman datos directamente en el dominio del tiempo sin un procesamiento preliminar. Originalidad: esta investigación servirá de referente para posteriores desarrollos como el diagnóstico de pacientes utilizando señales biológicas. En este documento se busca observar las características que presentan las máquinas de soporte vectorial para la clasificación de un sistema caótico. Limitaciones: no se realiza un procesamiento preliminar de datos por lo cual la clasificación está sujeta por los valores obtenidos directamente de la simulación

A proof-of-concept study on the use of a fluorescein-based 18F-tracer for pretargeted PET

BACKGROUND: Pretargeted immuno-PET tumor imaging has emerged as a valuable diagnostic strategy that combines the high specificity of antibody-antigen interaction with the high signal and image resolution offered by short-lived PET isotopes, while reducing the irradiation dose caused by traditional (89)Zr-labelled antibodies. In this work, we demonstrate proof of concept of a novel ‘two-step’ immuno-PET pretargeting approach, based on bispecific antibodies (bsAbs) engineered to feature dual high-affinity binding activity for a fluorescein-based (18)F-PET tracer and tumor markers. RESULTS: A copper(I)-catalysed click reaction-based radiolabeling protocol was developed for the synthesis of fluorescein-derived molecule [(18)F]TPF. Binding of [(18)F]TPF on FITC-bearing bsAbs was confirmed. An in vitro autoradiography assay demonstrated that [(18)F]TPF could be used for selective imaging of EpCAM-expressing OVCAR3 cells, when pretargeted with EpCAMxFITC bsAb. The versatility of the pretargeting approach was showcased in vitro using a series of fluorescein-binding bsAbs directed at various established cancer-associated targets, including the pan-carcinoma cell surface marker EpCAM, EGFR, melanoma marker MCSP (aka CSPG4), and immune checkpoint PD-L1, offering a range of potential future applications for this pretargeting platform. CONCLUSION: A versatile pretargeting platform for PET imaging, which combines bispecific antibodies and a fluorescein-based (18)F-tracer, is presented. It is shown to selectively target EpCAM-expressing cells in vitro and its further evaluation with different bispecific antibodies demonstrates the versatility of the approach. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41181-022-00155-2

Ultrafast Photoclick Reaction for Selective 18F-Positron Emission Tomography Tracer Synthesis in Flow

The development of very fast, clean, and selective methods for indirect labeling in PET tracer synthesis is an ongoing challenge. Here we present the development of an ultrafast photoclick method for the synthesis of short-lived 18F-PET tracers based on the photocycloaddition reaction of 9,10-phenanthrenequinones with electron-rich alkenes. The respective precursors are synthetically easily accessible and can be functionalized with various target groups. Using a flow photo-microreactor, the photoclick reaction can be performed in 60 s, and clinically relevant tracers for prostate cancer and bacterial infection imaging were prepared to demonstrate practicality of the method

Modular Medical Imaging Agents Based on Azide-Alkyne Huisgen Cycloadditions:Synthesis and Pre-Clinical Evaluation of(18)F-Labeled PSMA-Tracers for Prostate Cancer Imaging

Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide–alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide–alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre-clinical in vivo evaluation of fluorine-18- labeled PSMA-targeting ‘F-PSMA-MIC’ radiotracers (t1/2=109.7 min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [68Ga]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents

Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot Reduction/Cross-Coupling Procedure

The synthesis of functionalized (benz)aldehydes, via a two-step, one-pot procedure, is presented. The method employs a stable aluminum hemiaminal as a tetrahedral intermediate, protecting a latent aldehyde, making it suitable for subsequent cross-coupling with (strong nucleophilic) organometallic reagents, leading to a variety of alkyl and aryl substituted benzaldehydes. This very fast methodology also facilitates the effective synthesis of a 11C radiolabeled aldehyde. Aluminum-ate complexes enable transmetalation of alkyl fragments onto palladium and subsequent cross-coupling

Palladium-catalysed cross-coupling of lithium acetylides

The incorporation of alkynes into organic molecules is one of the most valuable transformations for the formation of C–C bonds and provides a versatile handle for further modifications. The Sonogashira cross-coupling of acetylenes holds a prominent position among the suite of catalytic cross-coupling reactions that are key to modern synthesis. Here we present a method that is complementary to the Sonogashira reaction, demonstrating cross-coupling of lithium acetylides with aryl bromides. The reactions take place under ambient conditions with short reaction times, affording the corresponding aryl acetylenes in good to excellent yields while displaying a remarkable functional group tolerance for an organolithium reaction, allowing the presence of a variety of organolithium-sensitive carbonyl functionalities. This developed cross-coupling methodology offers ample opportunities to access a wide variety of acetylenes, as is illustrated by the facile preparation of key intermediates for chemical biology and optoelectronic materials. [Figure not available: see fulltext.