Click chemistry PET imaging tracks antisense drug distribution in the brain

Assessing the distribution of a medication in the brain is critical for the treatment of a vast range of neurological disorders, especially conditions such as Parkinson’s and Alzheimer’s diseases. To that end, scientists in the United States and Sweden are developing a method to image therapeutic antisense oligonucleotides in the brain by relying on “click chemistry,” a Nobel Prize-winning technique in which molecules are linked—clicked together—like molecular Lego blocks.

Scientists predict that antisense oligonucleotides may soon be able to treat a number of neurological disorders. Antisense oligonucleotides are short synthetic strands of DNA or RNA that bind to a specific mRNA sequence. The problem currently facing scientists hoping to exploit the therapeutic promise is that a critical drawback overshadows their use: Antisense oligonucleotides must be able to penetrate the central nervous system and disperse evenly within the targeted tissue.

To date, it has been difficult for scientists to harness the distribution of antisense oligonucleotides, particularly in the brain. Click chemistry might help overcome that obstacle, collaborators in the new study say.

“Determination of a drug’s biodistribution is critical to ensure that it reaches the target tissue of interest,” writes Dr. Brendon E. Cook, lead author of the research. “This is particularly challenging in the brain, where invasive sampling methods may not be possible.”

The animal model study, published in the journal Science Translational Medicine, suggests that not only do antisense oligonucleotides have the potential to treat serious brain disorders, it is possible to trace their biodistribution in the brain through click chemistry.

Cook is a senior scientist at Biogen, a biotechnology company in Cambridge, Massachusetts, that specializes in the development of therapies to treat neurological conditions. The Biogen team worked with scientists at the Karolinska Institute in Sweden to develop the antisense oligonucleotides and test click chemistry. Cook specializes in click chemistry and tracers for the scanning technology known as PET (positron emission tomography).

He and colleagues developed a PET imaging methodology that tracks antisense oligonucleotides with a newly developed tracing molecule, [¹⁸F]BIO-687. This molecule reveals the distribution of a chosen, modified antisense oligonucleotide using click chemistry.

In 2022, the Nobel Prize in Chemistry was awarded to Carolyn Bertozzi of Stanford University, who founded the field of biorthogonal chemistry, also known as click chemistry. She shared the Nobel with Morten Meldal, a professor of chemistry at the University of Copenhagen, and Karl Barry Sharpless, a former professor of chemistry at MIT and Stanford University.

Meldal developed the CuAAC click reaction concurrently with Sharpless, but independent of him. The CuAAC reaction is a copper-catalyzed process that produces a 1,2,3-triazole, which Sharpless calls “the premier example of a click reaction.”

In the research by Cook and colleagues, molecular building blocks that “clicked together” fused two separate compounds. The researchers found that the new tracer, [¹⁸F]BIO-687, distributed well throughout the central nervous system of lab rats and was capable of effectively binding strongly to a test antisense oligonucleotide.

“PET imaging in rats demonstrated that the tracer had good kinetic properties for PET imaging in the rodent central nervous system and could react to form a covalent linkage with high specificity to the methyltetrazine-conjugated antisense oligonucleotide in vivo,” Cook explained, noting that an additional part of the study was conducted in non-human primates.

“Furthermore, the amount of PET tracer reacted by cycloaddition with the methyltetrazine was determined to be dependent on the concentration of antisense-oligonucleotide/methyltetrazine in rat brain tissue, as determined by comparing the PET imaging signal with the liquid chromatography–mass spectrometry signal in the tissue homogenates,” Cook continued.

He and his colleagues also found that the same approach which efficiently tracked the distribution of the antisense oligonucleotide in rats worked well in macaques. A second candidate therapeutic called BIIB080 also worked well in macaques, according to data in the study.

“The modular nature of the tracer…allows for a low-profile, biocompatible modification to be applied to a wide range of macromolecules,” Cook and colleagues concluded.

© 2025 Science X Network

Assessing the distribution of a medication in the brain is critical for the treatment of a vast range of neurological disorders, especially conditions such as Parkinson’s and Alzheimer’s diseases. To that end, scientists in the United States and Sweden are developing a method to image therapeutic antisense oligonucleotides in the brain by relying on “click chemistry,” a Nobel Prize-winning technique in which molecules are linked—clicked together—like molecular Lego blocks.

Scientists predict that antisense oligonucleotides may soon be able to treat a number of neurological disorders. Antisense oligonucleotides are short synthetic strands of DNA or RNA that bind to a specific mRNA sequence. The problem currently facing scientists hoping to exploit the therapeutic promise is that a critical drawback overshadows their use: Antisense oligonucleotides must be able to penetrate the central nervous system and disperse evenly within the targeted tissue.

To date, it has been difficult for scientists to harness the distribution of antisense oligonucleotides, particularly in the brain. Click chemistry might help overcome that obstacle, collaborators in the new study say.

“Determination of a drug’s biodistribution is critical to ensure that it reaches the target tissue of interest,” writes Dr. Brendon E. Cook, lead author of the research. “This is particularly challenging in the brain, where invasive sampling methods may not be possible.”

The animal model study, published in the journal Science Translational Medicine, suggests that not only do antisense oligonucleotides have the potential to treat serious brain disorders, it is possible to trace their biodistribution in the brain through click chemistry.

Cook is a senior scientist at Biogen, a biotechnology company in Cambridge, Massachusetts, that specializes in the development of therapies to treat neurological conditions. The Biogen team worked with scientists at the Karolinska Institute in Sweden to develop the antisense oligonucleotides and test click chemistry. Cook specializes in click chemistry and tracers for the scanning technology known as PET (positron emission tomography).

He and colleagues developed a PET imaging methodology that tracks antisense oligonucleotides with a newly developed tracing molecule, [¹⁸F]BIO-687. This molecule reveals the distribution of a chosen, modified antisense oligonucleotide using click chemistry.

In 2022, the Nobel Prize in Chemistry was awarded to Carolyn Bertozzi of Stanford University, who founded the field of biorthogonal chemistry, also known as click chemistry. She shared the Nobel with Morten Meldal, a professor of chemistry at the University of Copenhagen, and Karl Barry Sharpless, a former professor of chemistry at MIT and Stanford University.

Meldal developed the CuAAC click reaction concurrently with Sharpless, but independent of him. The CuAAC reaction is a copper-catalyzed process that produces a 1,2,3-triazole, which Sharpless calls “the premier example of a click reaction.”

In the research by Cook and colleagues, molecular building blocks that “clicked together” fused two separate compounds. The researchers found that the new tracer, [¹⁸F]BIO-687, distributed well throughout the central nervous system of lab rats and was capable of effectively binding strongly to a test antisense oligonucleotide.

“PET imaging in rats demonstrated that the tracer had good kinetic properties for PET imaging in the rodent central nervous system and could react to form a covalent linkage with high specificity to the methyltetrazine-conjugated antisense oligonucleotide in vivo,” Cook explained, noting that an additional part of the study was conducted in non-human primates.

“Furthermore, the amount of PET tracer reacted by cycloaddition with the methyltetrazine was determined to be dependent on the concentration of antisense-oligonucleotide/methyltetrazine in rat brain tissue, as determined by comparing the PET imaging signal with the liquid chromatography–mass spectrometry signal in the tissue homogenates,” Cook continued.

He and his colleagues also found that the same approach which efficiently tracked the distribution of the antisense oligonucleotide in rats worked well in macaques. A second candidate therapeutic called BIIB080 also worked well in macaques, according to data in the study.

“The modular nature of the tracer…allows for a low-profile, biocompatible modification to be applied to a wide range of macromolecules,” Cook and colleagues concluded.

© 2025 Science X Network