Novel radiolabeling method shows promise for PET imaging

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The ability to bind highly stable aluminum (Al) fluorine-18 (18F) to metal-binding ligands is a promising new labeling method that should be applicable to a diverse array of molecules for PET, according to a study published online May 14 in the Journal of Nuclear Medicine.

Small biomolecules are typically radiolabeled with 18F by binding it to a carbon atom, a process that usually is designed uniquely for each new molecule and requires several steps and hours to produce. William J. McBride, MD, from the Morris Plains, N.J.-based Immunomedics, and Robert M. Sharkey, MD, from the Center for Molecular Medicine and Immunology, Garden State Cancer Center in Belleville, N.J., along with their colleagues, reported on a facile method wherein 18F is first attached to aluminum as Al18F and then bound to a chelate attached to a peptide. The result is the formation of a stable Al18F-chelate-peptide complex in an efficient one-pot process, according to the investigators.

For proof of principle, the researchers applied this method to a peptide suitable for use in a bispecific antibody pretargeting method. A solution of AlCl3·6H2O in a pH 4.0 sodium-acetate buffer was mixed with an aqueous solution of 18F to form the Al18F complex. This was added to a solution of IMP 449 (NOTA-p-Bn-CS-D-Ala-D-Lys(HSG)-D-Tyr-D-Lys(HSG)-NH2) (NOTA-p-Bn-CS is made from S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid; HSG is histamine-succinyl-glycine) and heated to 100°C for 15 minutes. In vitro and in vivo stability and targeting ability of the Al18F-IMP 449 were examined in nude mice bearing LS174T human colonic tumors pretargeted with an anti-CEACAM5 bispecific antibody (TF2).

The researchers reported that radiolabeled peptide was produced in 5 to 20 percent yield with an estimated specific activity of 18,500-48,100 GBq (500-1,300 Ci)/mmol. The Al 18F-IMP 449 was stable for four hours in serum in vitro, and in animals, activity isolated in the urine 30 minutes after injection was bound to the peptide.

According to the authors, nonchelated Al 18F had higher tissue uptake, particularly in the bones, than the chelated Al 18F-IMP 449, which cleared rapidly from the body by urinary excretion. Tumor uptake was 30-fold higher with TF2-pretargeted Al 18F-IMP 449 than with the peptide alone.

They found that dynamic PET showed tumor localization within 30 minutes and rapid and thorough clearance from the body.

McBride and colleagues said that the Al18F complex is stable, but the more arduous task was finding a suitable linker for stable binding to various compounds. "Several of the more commonly used chelating agents were examined, but although some would capture Al18F (even quantitatively), most were not sufficiently stable for in vivo applications," the authors wrote.

They concluded that NOTA provided the first indication that the Al18F complex could be bound stably, and noted that mass spectroscopy analysis suggests that the Al18F complex is held in place by the three nitrogens and two of the carboxyl groups. "It is also important to note that while the labeling process reported here added a preformed Al18F complex to the chelatepeptide, we also were able to bind 18F to aluminum that was preloaded in the NOTA-IMP 449," the authors wrote

Nevertheless, the researchers noted that studies lay the foundation for a new, simplified 18F-labeling method that could allow many more compounds to be prepared with 18F PET tracer.

The National Institute of Biomedical Imaging and BioEngineering of the U.S. National Institutes of Health (NIH) supported the study in part with a grant.