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.
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
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.
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-
Cformamides would enable access to this important class of compounds as in vivo PET imaging agents.
A novel radiolabelling strategy for the synthesis of carbon-11 radiolabelled formamides (
Cformamides) is presented. The reaction proceeded with the conversion of a primary amine to the corresponding
Cisocyanate using cyclotron-produced
CCO
, a phosphazene base (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, BEMP) and phosphoryl chloride (POCl
). The
Cisocyanate was subsequently reduced to
Cformamide using sodium borohydride (NaBH
).
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
Cformyl methionine (RCY = 48%).
This study demonstrates the feasibility of
C-formylation of primary amines with the primary synthon
CCO
. 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.
The receptor for advanced glycation end products (RAGE) is a viable target for early Alzheimer's disease (AD) diagnosis using positron emission tomography (PET) as RAGE overexpression precedes Aβ ...plaque formation. The development of a carbon-11 analog of FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide,
CFPS-ZM1), possessing nanomolar affinity for RAGE, may enable the imaging of RAGE for early AD detection.
Herein we report an optimized
CCO
-to-
CCO chemical conversion for the synthesis of
CFPS-ZM1 and
brain autoradiography. The
CCO
-to-
CCO conversion via
C-silanecarboxylate derivatives was achieved with a 57% yield within 30 s from end of
CCO
delivery.
CFPS-ZM1 was obtained with a decay-corrected isolated radiochemical yield of 9.5%.
CFPS-ZM1 distribution in brain tissues of wild-type versus transgenic AD model mice showed no statistically significant difference and high nondisplaceable binding.
PDF
![Radiolabeling of [11C]FPS-Z...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1756-8919_1756-8927/small "Radiolabeling of [11C]FPS-ZM1, a receptor for advanced glycation end products-targeting positron emission tomography radiotracer, using a [11C]CO2-to-[11C]CO chemical conversion")