Late-stage 11C-carbonylation of drug-like molecules for PET

Positron emission tomography (PET) is a non-invasive in vivo imaging technique used for translational biomedical research and clinical diagnosis. A fundamental pre-condition for PET is the radiolabelled tracer molecule used in the emission measurement, and there is a pressing need to accelerate the development of novel PET tracers to meet an increasing demand from the healthcare system, academia and drug industry. A cornerstone in this effort is access to methodologies for late-stage isotopic labelling of small molecules with the positron-emitting radionuclide carbon-11 (11C, half-life 20.4 min). The carbonyl group is one of the most abundant motifs in biologically important molecules and therefore a good target for isotopic labelling. The aim of this thesis was to develop 11Ccarbonylation reactions that made use of [11C]carbon dioxide ([11C]CO2), a synthon obtained directly from medical cyclotrons. The incorporation of this radiolabelled synthon, first into model compounds and later into biologically relevant molecules, was accomplished in automated radiochemistry systems and analysed using liquid chromatography. Papers I and II describe the development of two different methods for the synthesis of 11Clabelled cyclic ureas. In Paper I, the noteworthy concept of CO2 fixation with strong, organic bases was applied. A set of [11C]benzimidazolones was thus radiolabelled with high radiochemical yields under mild conditions. In Paper II, the task was approached by using a click chemistry-inspired Staudinger/aza-Wittig cascade reaction. A wide selection of five and six-membered cyclic ureas was radiolabelled using this simple one-pot reaction. As a proof of concept, the β-adrenergic radioligand, (S)-[11C]CGP12177, was eventually produced using both methods. Paper III showcased a novel 12C/11C isotopic exchange reaction for labelling of phenylacetic acids. The method is based on heat-induced decarboxylation of the substrate molecule, followed by introduction of isotope-labelled [11C]CO2, without need for any additional reagents. Three small molecules, including two anti-inflammatory drugs, were labelled to prove suitability of the method for a low-concentration carbon-11 source. In Paper IV, the CO2 fixation concept was applied to the preparation of 11C-labelled oxazolidinones and other cyclic urethanes, starting from corresponding anilines, benzylamines and dibromoalkanes. Five and six-membered cyclic urethanes, as well as both phenylic and benzylic compounds, were labelled with moderate to excellent radiochemical yields. In conclusion, a set of new methodologies was developed for the 11C-labelling of carbonyl groups. Each of the novel methodologies utilised [11C]CO2 obtained directly from a medical cyclotron without further chemical manipulation, and were successfully used in the preparation of cyclic ureas, benzoxazolone and benzothiazolone compounds, phenylacetic acids, Naryloxazolidinones, N-aryloxazinanones and N-benzyloxazinanones. Given the useful radiochemical yields and operational simplicity of these methods, there is a reason to be optimistic about their adoption in future PET tracer development

I. Meyer-Schuster rearrangement, II. Synthesis of potential FtsZ inhibitors

I. Meyer-Schuster rearrangement Meyer-Schuster rearrangement is an atom economical reaction, in which α,β-unsaturated carbonyl compounds are formed from propargylic alcohols and their derivatives by formal migration of the carbonyl group. Brønsted acids have been used traditionally as stoichiometric catalysts, but more recently, several Lewis acids both salts and metal complexes, have become popular due to their selectivity and mild conditions applied. Also oxo-metal complexes are often used despite the high reaction temperature needed. In this thesis, various manners and catalysts for the Meyer-Schuster rearrangement are reviewed. Reactivity of different substrates and practicality of several types of catalysts are evaluated. In addition, different reaction mechanisms are discussed, as they are highly substrate and catalyst-dependent. Propargylic alcohols have two functional groups, in which the catalysts can coordinate according to their characteristics. Especially gold compounds, which are soft Lewis acids, have gained interest due to their specific coordination ability. II. Synthesis of potential FtsZ inhibitors FtsZ, which is a bacterial homologue for tubulin, is essential in the cell division. It polymerizes into a dynamic ring structure, which constricts to separate the new daughter cells. Being FtsZ protein-directing compounds, 3-methoxybenzamide derivatives have been noticed to inhibit growth of certain bacteria. In this work, a set of molecules was synthesized based on PC190723, which is a 3-methoxybenzamide derivative. In order to study interactions between the protein and the inhibitors, fluorescent groups were attached. Polymer sedimentation tests and fluorescence spectroscopy were used to study shortly the biological behavior of the products. It was discovered that one of the products is a polymer-stabilizing and thus, FtsZ activity inhibiting compound

Synthesis, Stability and Relaxivity of TEEPO-Met : An Organic Radical as a Potential Tumour Targeting Contrast Agent for Magnetic Resonance Imaging

Cancer is a widespread and life-threatening disease and its early-stage diagnosis is vital. One of the most effective, non-invasive tools in medical diagnostics is magnetic resonance imaging (MRI) with the aid of contrast agents. Contrast agents that are currently in clinical use contain metals, causing some restrictions in their use. Also, these contrast agents are mainly non-specific without any tissue targeting capabilities. Subsequently, the interest has notably increased in the research of organic, metal-free contrast agents. This study presents a new, stable organic radical, TEEPO-Met, where a radical moiety 2,2,6,6-tetraethylpiperidinoxide (TEEPO) is attached to an amino acid, methionine (Met), as a potentially tumour-targeting moiety. We describe the synthesis, stability assessment with electron paramagnetic resonance (EPR) spectroscopy and relaxation enhancement abilities by an in vitro nuclear magnetic resonance (NMR) and phantom MRI studies of TEEPO-Met. The new compound proved to be stable notably longer than the average imaging time in conditions mimicking a biological matrix. Also, it significantly reduced the relaxation times of water, making it a promising candidate as a novel tumour targeting contrast agent for MRI.Peer reviewe

Late-stage isotopic carbon labeling of pharmaceutically relevant cyclic ureas directly from CO2

International audienceA robust, click chemistry inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (11C, 13C, 14C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple, reproducible in different radiochemistry centers, exhibits a remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency

Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

International audienceA transition-metal-free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO2, this protocol allows the carbon isotope to be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes [ 14 C] and [ 13 C]. A proof of concept with [ 11 C] was also obtained with low molar activities valuable for distribution studies