The receptor for advanced glycation endproducts (RAGE) is an ubiquitous, transmembrane, immunoglobulin-like receptor that exists in multiple isoforms and binds to a diverse range of endogenous ...extracellular ligands and intracellular effectors. Ligand binding at the extracellular domain of RAGE initiates a complex intracellular signaling cascade, resulting in the production of reactive oxygen species (ROS), immunoinflammatory effects, cellular proliferation, or apoptosis with concomitant upregulation of RAGE itself. To date, research has mainly focused on the correlation between RAGE activity and pathological conditions, such as cancer, diabetes, cardiovascular diseases, and neurodegeneration. Because RAGE plays a role in many pathological disorders, it has become an attractive target for the development of inhibitors at the extracellular and intracellular domains. This review describes the role of endogenous RAGE ligands/effectors in normo- and pathophysiological processes, summarizes the current status of exogenous small-molecule inhibitors of RAGE and concludes by identifying key strategies for future therapeutic intervention.
Background
Formamides are common motifs of biologically-active compounds (e.g. formylated peptides) and are frequently employed as intermediates to yield a number of other functional groups. A rapid, ...simple and reliable route to
carbonyl
-
11
Cformamides would enable access to this important class of compounds as in vivo PET imaging agents.
Results
A novel radiolabelling strategy for the synthesis of carbon-11 radiolabelled formamides (
11
Cformamides) is presented. The reaction proceeded with the conversion of a primary amine to the corresponding
11
Cisocyanate using cyclotron-produced
11
CCO
2
, a phosphazene base (2-
tert
-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, BEMP) and phosphoryl chloride (POCl
3
). The
11
Cisocyanate was subsequently reduced to
11
Cformamide using sodium borohydride (NaBH
4
).
11
CBenzyl formamide was obtained with a radiochemical yield (RCY) of 80% in 15 min from end of cyclotron target bombardment and with an activity yield of 12%. This novel method was applied to the radiolabeling of aromatic and aliphatic formamides and the chemotactic amino acid
11
Cformyl methionine (RCY = 48%).
Conclusions
This study demonstrates the feasibility of
11
C-formylation of primary amines with the primary synthon
11
CCO
2
. The reactivity is proportional to the nucleophilicity of the precursor amine. This novel method can be used for the production of biomolecules containing a radiolabelled formyl group.
Positron emission tomography (PET) is a powerful functional imaging technique that requires the use of positron emitting nuclides. Carbon-11 (
11
C) radionuclide has several advantages related to the ...ubiquity of carbon atoms in biomolecules and the conservation of pharmacological properties of the molecule upon isotopic exchange of carbon-12 with carbon-11. However, due to the short half-life of
11
C (20.4 minutes) and the low scale with which it is produced by the cyclotron (sub-nanomolar concentrations), quick, robust and chemospecific radiolabelling strategies are required to minimise activity loss during incorporation of the
11
C nuclide into the final product. To address some of the constraints of working with
11
C, the use of silicon-based chemistry for
11
C-labelling was proposed as a rapid and effective route for radiopharmaceutical production due to the broad applicability and high efficiency showed in organic chemistry. In the past years several organic chemistry methodologies have been successfully applied to
11
C-chemistry. In this short review, we examine silicon-based
11
C-chemistry, with a particular emphasis on the radiotracers that have been successfully produced and potential improvements to further expand the applicability of silicon in radiochemistry.
The use of silicon-based reagents and precursors for carbon-11 labelling has shown wide applicability and robustness with short reaction times using mild conditions. In this review, recent advances and future perspectives are examined.
A novel carboxylation radiosynthesis methodology is described starting from cyclotron-produced 11CCO2 and fluoride-activated silane derivatives. Six carbon-11 labelled carboxylic acids were obtained ...from their corresponding trimethylsilyl and trialkoxysilyl precursors in a one-pot labelling methodology. The radiochemical yields ranged from 19% to 93% within 12 minutes post 11CCO2 delivery with a trapping efficiency of 21–89%.
A novel carboxylation radiosynthesis methodology is described starting from cyclotron-produced
CCO
and fluoride-activated silane derivatives. Six carbon-11 labelled carboxylic acids were obtained ...from their corresponding trimethylsilyl and trialkoxysilyl precursors in a one-pot labelling methodology. The radiochemical yields ranged from 19% to 93% within 12 minutes post
CCO
delivery with a trapping efficiency of 21-89%.
A simple and rapid carbon-11 carboxylation radiosynthesis method.
A novel carboxylation radiosynthesis methodology is described starting from cyclotron-produced
11
CCO
2
and fluoride-activated ...silane derivatives. Six carbon-11 labelled carboxylic acids were obtained from their corresponding trimethylsilyl and trialkoxysilyl precursors in a one-pot labelling methodology. The radiochemical yields ranged from 19% to 93% within 12 minutes post
11
CCO
2
delivery with a trapping efficiency of 21–89%.
The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has ...increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.
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