RADIOCHEMISTRY
PET projects improve 11C imaging agents Researchers devise versatile synthetic strategies for making new radiolabeled compounds When you get a positron emission tomography (PET) scan, the medical procedure begins minutes beforehand when a chemist prepares a radioactive imaging agent starting from a simple isotope-labeled compound created in a cyclotron. Radiation given off by the imaging agent, which is 11CF
3 labeling
11CH 4
CoF3
11CHF
Iodinated fluoxetine 3
Fluoroform
CH3
[Cu11CF3]
11CN labeling
I
SH Peptide
Pd I
L
S H11CN
Peptide
L = phosphine ligand
typically a sugar, peptide, or other so-called reporter biomolecule, can be tracked as the agent travels through your body, allowing for the assessment of drug distribution, protein expression, and metabolism to diagnose disease and monitor your health. During the past few years, chemists have reported a number of synthetic breakthroughs making 18F-labeled compounds. Fluorine can improve the performance of
imaging agents by helping the compounds reach their targets. And 18F has a half-life of about 110 minutes, versus only about 20 minutes for 11C, the other commonly used PET isotope, providing more time to prepare the imaging agent. Two research groups have now devised synH N thetic strategies that offer more flexible O routes to 11C-labeled compounds. 11CF 3 Mohammad B. Fluoxetine Haskali and Victor W. Pike of the U.S. National Institute of 11CN Mental Health’s Molecular Imaging Branch have developed the first method for preparing 11C-labeled fluoroform, 11CHF3, and used the reagent to incorporate labeled trifluoromethyl groups into imaging agents (Chem.–Eur. J. 2017, DOI: 10.1002/chem.201701701). Haskali and Pike found that cobalt trifluoride readily fluorinates 11CH4 to 11CHF3, which the researchers then used to prepare a copper transfer reagent for incorporating 11CF groups into model compounds such 3 as benzophenone and known drugs such as the antidepressant fluoxetine (Prozac). Start to finish, the synthesis takes less than 20 minutes and achieves a higher level of radioactivity, and therefore potentially bet-
ter PET image quality, than is possible by starting with 18F-labeled fluoroform. Chemists have focused on generating 18 F-labeled CF3 groups, but due to the quirks of 18F chemistry, only modest radioactivity in imaging agents has been achieved, notes PET radiochemist Philip Miller of Imperial College London. “This paper describes a really novel workaround to the molar activity issue by using 11C-labeled fluoroform,” Miller says. “This will be a real boon for those needing to develop PET probes with CF3 groups and demonstrates the versatility of 11C as an isotope for PET tracers.” In a second achievement, a team led by MIT synthetic chemist Stephen L. Buchwald and Harvard Medical School radiochemist Jacob M. Hooker have devised a palladium-mediated cross-coupling reaction that uses 11C-labeled hydrogen cyanide, H11CN, as a reagent. The team directly labeled nanomolar amounts of unmodified peptides with 11C cyano groups in less than 15 minutes under mild conditions (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b02761). The approach demonstrates “some very clever” 11C coupling chemistry that opens up new possibilities for peptide labeling, Miller says. Carbon-11 is not commonly used for peptide labeling because of the chemical and time challenges, Miller adds. “Not only are these new 11C-labeling reactions fast and selective on the peptide, the team has also proved that the labeling system is workable under high-activity synthesis.”—STEVE RITTER
PHYSICAL CHEMISTRY
X-rays induce electron-gobbling ‘black holes’ High-intensity, hard X-ray pulses induce extreme ionization of heavy atoms, turning them into a kind of “black hole” within molecules, according to new research. The ionized atoms suck electrons in from neighboring atoms before the molecule falls apart (Nature 2017, DOI: 10.1038/nature22373). To solve macromolecular structures such as those of proteins, crystallographers frequently incorporate transition metals and other heavy atoms into crystals to help with data analysis. But as researchers develop free-electron lasers to use ultra intense, femtosecond X-ray pulses to improve crystal structure data, questions remain about how those X-ray pulses interact with heavy
atoms to cause radiation damage that alters or destroys the sample. Using SLAC National Accelerator Laboratory’s Linac Coherent Light Source and theoretical analysis, a team led by Artem Rudenko of Kansas State University and Sang-Kil Son of Germany’s Deutsches Elektronen Synchrotron particle accelerator studied the effects of ultra intense X-ray pulses on xenon atoms and iodine-containing molecules. The 30-femtosecond laser pulses packed a walloping 2 × 1019 Watts/ cm2 with photon energies of 8.3 keV. The pulses ionized the xenon atoms (n = 54) to a charge state of +48 and, surprisingly, the iodine atoms (n = 53) to a state
of +47. An iodomethane molecule gained an overall charge state of +54. This result contrasts with soft or less-intense hard X-ray experiments, in which isolated heavy atoms were ionized more than those bound within a molecule. According to the researchers’ simulations, as the higher-intensity, hard X-ray pulses cause iodine to lose more electrons, intramolecular electron transfer also occurs to effectively shift negative charge from the rest of the molecule to the iodine. But because the electron transfer occurs faster than the X-ray pulse duration, the transferred electrons are also stripped from the iodine site.—JYLLIAN KEMSLEY JUNE 5, 2017 | CEN.ACS.ORG | C&EN
5
