INTRO SENTENCE:
UCLA researchers in the Department of Molecular and Medical Pharmacology have developed a thiol-reactive, site-specific radiolabeling of small molecules and biomolecules for positron emission tomography (PET) molecular imaging.
TITLE:
Mild and site-selective 18F-labeling of small molecules and/or biomolecules via thiol-reactive synthon
BACKGROUND:
Positron Emission Tomography (PET) is a sensitive, high resolution and tissue accretion imaging modality used to identify and evaluate various diseases including: cancers, heart disease and brain disorders. PET scans allow early diagnosis of diseases before they show up in other imaging procedures. PET, however, requires the use of positron-emitting radionuclides, most commonly fluorine-18 (18F), which is introduced into the body prior to imaging. The radioactive ligand must be conjugated to a biologically active molecule, such as glucose, that binds to the receptor target or site of action.
The current gold-standard for conjugating positron-emitting radio nucleotides involves reactions that enable a site-selective thiol linkage via Michael addition between a sulfhydryl and a maleimide group. Theses conjugates, however, exhibit low stability in physiological conditions and are susceptible to a Retro-Michael addition reaction, meaning the conjugate can turn back into the free sulfhydryl and maleimide synthon. In this reversible reaction, other thiol-containing molecules can then have the opportunity to react with the now available maleimide, resulting in unwanted side-products that can affect PET diagnosis and quantification.
To overcome the instability issues, other types of thioether linkages have been reported, most notably tosylates, bromo- and iodo-acetyls. However, these options have lower reaction rates with thiol and also high reactivity with other amino acids. In addition, the synthesis and purification of the reported thiol-reactive synthon is lengthy, causing low yields of the final product. Thus, there’s a need to develop stable, easy to produce positron-emitting nuclides to further the diagnostic and associated powers of PET technologies.
INNOVATION:
UCLA researchers led by Prof. Jennifer Murphy have developed a thiol-reactive synthesis method and conjugates that display a number of advantages over conventional molecules and technologies. The developed thiol-reactive synthons can be made in one-step with only one HPLC purification and are easy to characterize via HPLC, providing 89-93% yields and short production times. In addition, the synthons are more stable than conventional 18F-vinyl sulfones that have the F-18 bound to an alkyl carbon chain, which is known to be less stable in vivo than the F-18 being bound to an aromatic carbon ring. In the developed synthon, the F-18 is bound to the aromatic carbon ring in order to make them more stable in vivo.
POTENTIAL APPLICATIONS:
• Novel site-selective compounds and production methods for PET imaging
ADVANTAGES:
• Site selective conjugation to biomolecules via thiol-based chemistry
• Stable bioconjugation with the F-18 being bound to an aromatic carbon ring
• High yields of final compounds with 89-93% yields
• One-step reaction with only one HPLC purification
DEVELOPMENT-TO-DATE:
This synthon was synthesized using the proposed method and shown to bind to thiol-containing amino-acids.