Periodic Reporting for period 3 - FASTLabEx (Fast Radio-Labeling and Isotope Exchange)
Okres sprawozdawczy: 2023-10-01 do 2025-03-31
Humans are surrounded by a dazzling array of synthetic organic molecules. Their impact on improving life quality and lifestyle is beyond doubt. Thus, it is of fundamental importance to accurately detect and quantify the fate of organic compounds and provide a precise risk/benefit assessment before they reach the market and large public exposure.
The insertion of isotopic labels onto organic molecules is a well-recognized tool to track the faith of synthetic organic compounds and unveil their behavior both in the environment and in vitro or in vivo. The choice of a specific isotope is dictated by a multiplicity of factors, such as the energy of particles emitted over its radioactive decay, its half-life, the type of application and, in case where multiple options are available, the ease of synthetic access to the desired radiotracer. As carbon is omnipresent and at the foundation of life on earth, the insertion of carbon isotope label(s) into organic compounds has received extensive attention over the past century, but has heavily relied on lengthy multi-step processes.
The seemless incorporation of carbon-14 tracer (14C, - emitter, t1/2 = 5730 years) is a technology recognised as the gold standard. A rapid and straightforward synthetic access to carbon radiolabeled organic molecules is a strict requirement for accelerating research in these high societal impacting fields.
Surprisingly, carbon radiolabeling still represents a bottleneck and an unsolved fundamental problem. In contrast to stable and natural abundant carbon-12, the synthesis of organic molecules with carbon (radio)isotopes must be conceived and optimized in order to navigate through the hurdles of radiochemical requirements, such as high costs of the starting materials, harsh conditions and radioactive waste generation. In addition, it must initiate from the small cohort of available C-labeled building blocks. For long time, multi-step approaches have represented the sole available patterns.
These limitations are related to synthetic challenges associated to the radioisotope fundamental source, as carbon-14 is generated in nuclear reactors as Ba14CO3. This poorly soluble carbonate is routinely converted to carbon dioxide (14CO2): highly stable and poorly reactive building block. As a matter of fact, 14CO2 requires harsh reaction conditions for its functionalization, often not compatible with labile functional groups present on the majority of pharmaceuticals and agrochemicals. Other CO2-derived primary building blocks are K14CN, 14CH3I and acetylene (14C2H2). All these carbon sources are commonly used in a multi-step fashion. The radioactivity is incorporated into the chemical scaffold at an early stage of the synthesis and transformed, by a series of consecutive steps, into the desired molecule.
This poorly viable approach results in a limited number of new chemical entities (NCE) labeled with 14C in the pharmaceutical and agrochemical industries. Carbon-14 is often replaced in pre-clinical and early clinical phases by tritium (3H) labeling (cheaper and faster alternative), even though it is well know that carbon labeling is more stable to metabolism compared to hydrogen
On the other side, the development of chemical reactions based on the reversible cleavage of C-C bonds might offer new opportunities and reshape retrosynthetic analysis in radiosynthesis.
This ERC project envision the development of selective carbon isotope exchange (CIE) reactions. CIE would enable the synthesis of labeled compounds in a single operation without the need for precursors design and synthesis.
The underlying scientific question is whether a C-C bond can be selectively cleaved and replaced by a new C-14C bond, utilizing poorly reactive 14CO2 or other convenient isotope sources. Needless to say, the transformation should operate onto poly-functionalised molecules such as pharmaceuticals, under mild reaction conditions, thus preserving the integrity of the whole structure.
The development of such a technologies enhancing the speed and practicality of carbon labeling would:
- Help reducing drug attrition and erroneous evaluation of new chemical entities: enabling an early drug candidates selection, with reliable ADME data at metabolically safe positions for pharmaceuticals and veterinary drugs;
- Foster risk assessment of agrochemical entities;
- Enable an easier evaluation of the environmental impact of organic molecules.
The insertion of isotopic labels onto organic molecules is a well-recognized tool to track the faith of synthetic organic compounds and unveil their behavior both in the environment and in vitro or in vivo. The choice of a specific isotope is dictated by a multiplicity of factors, such as the energy of particles emitted over its radioactive decay, its half-life, the type of application and, in case where multiple options are available, the ease of synthetic access to the desired radiotracer. As carbon is omnipresent and at the foundation of life on earth, the insertion of carbon isotope label(s) into organic compounds has received extensive attention over the past century, but has heavily relied on lengthy multi-step processes.
The seemless incorporation of carbon-14 tracer (14C, - emitter, t1/2 = 5730 years) is a technology recognised as the gold standard. A rapid and straightforward synthetic access to carbon radiolabeled organic molecules is a strict requirement for accelerating research in these high societal impacting fields.
Surprisingly, carbon radiolabeling still represents a bottleneck and an unsolved fundamental problem. In contrast to stable and natural abundant carbon-12, the synthesis of organic molecules with carbon (radio)isotopes must be conceived and optimized in order to navigate through the hurdles of radiochemical requirements, such as high costs of the starting materials, harsh conditions and radioactive waste generation. In addition, it must initiate from the small cohort of available C-labeled building blocks. For long time, multi-step approaches have represented the sole available patterns.
These limitations are related to synthetic challenges associated to the radioisotope fundamental source, as carbon-14 is generated in nuclear reactors as Ba14CO3. This poorly soluble carbonate is routinely converted to carbon dioxide (14CO2): highly stable and poorly reactive building block. As a matter of fact, 14CO2 requires harsh reaction conditions for its functionalization, often not compatible with labile functional groups present on the majority of pharmaceuticals and agrochemicals. Other CO2-derived primary building blocks are K14CN, 14CH3I and acetylene (14C2H2). All these carbon sources are commonly used in a multi-step fashion. The radioactivity is incorporated into the chemical scaffold at an early stage of the synthesis and transformed, by a series of consecutive steps, into the desired molecule.
This poorly viable approach results in a limited number of new chemical entities (NCE) labeled with 14C in the pharmaceutical and agrochemical industries. Carbon-14 is often replaced in pre-clinical and early clinical phases by tritium (3H) labeling (cheaper and faster alternative), even though it is well know that carbon labeling is more stable to metabolism compared to hydrogen
On the other side, the development of chemical reactions based on the reversible cleavage of C-C bonds might offer new opportunities and reshape retrosynthetic analysis in radiosynthesis.
This ERC project envision the development of selective carbon isotope exchange (CIE) reactions. CIE would enable the synthesis of labeled compounds in a single operation without the need for precursors design and synthesis.
The underlying scientific question is whether a C-C bond can be selectively cleaved and replaced by a new C-14C bond, utilizing poorly reactive 14CO2 or other convenient isotope sources. Needless to say, the transformation should operate onto poly-functionalised molecules such as pharmaceuticals, under mild reaction conditions, thus preserving the integrity of the whole structure.
The development of such a technologies enhancing the speed and practicality of carbon labeling would:
- Help reducing drug attrition and erroneous evaluation of new chemical entities: enabling an early drug candidates selection, with reliable ADME data at metabolically safe positions for pharmaceuticals and veterinary drugs;
- Foster risk assessment of agrochemical entities;
- Enable an easier evaluation of the environmental impact of organic molecules.
Carbon Isotope Exchange (CIE) is a promising concept in radiolabeling. The selective replacement of molecular moieties into organic molecules, by reversible molecular deconstruction/reconstruction in presence of an appropriate radiolabeled moiety, will enable the access to labeled compounds in a single operation, directly from the end-use molecules.
Since its commencement, FASTLabEx aimed to provide a global answer to the underlying scientific question in CIE: “can C-C bonds be selectively cleaved and replaced by new C-14C bonds, in presence of an appropriate isotope source?”
Thus far, efforts have been focused on the use of different primary sources of carbon-14 and basic building blocks, namely:
1) carbon dioxide - 14CO2 : this readily available building block is particularly convenient;
2) carbon monoxide - 14CO : the chemistry of carbon monoxide is extremely rich and holds much promises for radiolabeling;
3) cyanide salts are easier to handle than gasseous14CO2 and 14CO, and are the more frequently utilized building blocks. Nitrile exchange will give access to a completely new variety of drugs and will benefit from the rich versatility of this functional group.
Since its commencement, FASTLabEx aimed to provide a global answer to the underlying scientific question in CIE: “can C-C bonds be selectively cleaved and replaced by new C-14C bonds, in presence of an appropriate isotope source?”
Thus far, efforts have been focused on the use of different primary sources of carbon-14 and basic building blocks, namely:
1) carbon dioxide - 14CO2 : this readily available building block is particularly convenient;
2) carbon monoxide - 14CO : the chemistry of carbon monoxide is extremely rich and holds much promises for radiolabeling;
3) cyanide salts are easier to handle than gasseous14CO2 and 14CO, and are the more frequently utilized building blocks. Nitrile exchange will give access to a completely new variety of drugs and will benefit from the rich versatility of this functional group.
Results obtained thus far in the context of FASTLabEx have shown a significant progress that goes far beyond the state of the art in the area of carbon isotope labeling.
The development of chemical reactions based on the reversible cleavage of C-C bonds offer new opportunities and reshape retrosynthetic analysis in radiosynthesis and FASTLabEx have provided effective opportunity for late-stage labeling. At present, CIE strategies have relied on the use of primary and easily accessible radiolabeled C1-building blocks, such as carbon dioxide, carbon monoxide and cyanides, while the activation principles have been based on thermal, photocatalytic, metal-catalyzed processes.
Besides the field of isotope labeling, the details study of equilibria in dynamic processes explore in this project (i.e. reversible carboxylation) provide data, which are expected to provide new insights in the study reaction mechanism.
The development of chemical reactions based on the reversible cleavage of C-C bonds offer new opportunities and reshape retrosynthetic analysis in radiosynthesis and FASTLabEx have provided effective opportunity for late-stage labeling. At present, CIE strategies have relied on the use of primary and easily accessible radiolabeled C1-building blocks, such as carbon dioxide, carbon monoxide and cyanides, while the activation principles have been based on thermal, photocatalytic, metal-catalyzed processes.
Besides the field of isotope labeling, the details study of equilibria in dynamic processes explore in this project (i.e. reversible carboxylation) provide data, which are expected to provide new insights in the study reaction mechanism.