1. The Design and Synthesis of DFO Derivatives for PET-Imaging
Aaron Chung, Dr. Mahmoud Abdalrahman, Dr. Roy Planalp
Department of Chemistry, University of New Hampshire
Durham, New Hampshire, 03824
3/18/18
Introduction
Positron Emission Tomography (PET) is a versatile clinical imaging technique that is used to detect various pathologies, including cancers. This technique measures physiological function by looking at blood flow, metabolism, neurotransmitters and radio-labeled drugs.1 The combination of whole-body physiological data and high-resolution imaging allows physicians to make a more accurate diagnosis, monitor treatment efficacy, and predict onset changes. The currently-employed ligand used for PET is desferrioxamine (DFO), which is a hexadentate bifunctional chelator. The preferred radioisotope for PET is 89Zr4+ due to its half-life of 78.4 hours, which matches the pharmacokinetics of immunoglobulins (3-4) days and a relatively low positron energy of keV.2 However, Zr4+ possesses a coordination number of eight, while DFO is hexadentate. Two binding sites on the metal will ultimately be exposed to solvent (H2O), which will promote demetallation, as a result of instability. The consequence of this instability results in unwanted toxicity accumulating in bone marrow as Zr is considered a “bone seeker”.3 To combat the osteophilic nature of Zr, a better ligand can be designed and synthesized, such that it fulfills all eight binding sites of 89Zr4+ while retaining its bifunctionality.
Conclusion
The success of the HATU coupling of DFO and AMA is inconclusive. The proton NMR exhibits shouldered peaks, which makes characterization difficult to explore. Solvent choice resulted in proton exchange, making desired peaks absent from interpretation. An appropriate signal to noise ratio on the carbon NMR has not yet been obtained. MALDI TOF, alone, is insufficient to make claims on a successful synthesis.
Aspirin anhydride was successfully synthesized, however, was too challenging to purify/isolate. Product appeared as a slight yellow glass and could not be isolated through various methods, such as filtration, recrystallization and column chromatography. Since the anhydride could not be isolated, the synthesis of a DFO derivative from the anhydride was not attempted.
The EDC coupling was successful in producing the desired product, however, starting material still resides within the product and impurities are clearly present.
Figure 1. 13C NMR of DFO coupled to Salicylic Acid
Future Work
Now that a promising DFO coupling has been found, we plan to improve the work-up in order to better the purity of the product, making the ligand bifunctional, and finally coordinating a zirconium complex with the newly designed and synthesized ligand.
Experimental
Multiple syntheses were performed in an attempt to yield an octadentate bifunctional ligand.
Scheme 1. HATU coupling of aminomalonic acid to desferrioxamine forming DFO-8
Scheme 2. EDC coupling of aspirin and desferrioxamine.
Scheme 3. Preparation of aspirin anhydride for coupling to DFO.
Scheme 4. Preparation of aspirin DFO derivative from corresponding anhydride.
Figure 2. 13C NMR of DFO Mesylate
Acknowledgements
I would like to thank the UNH Chemistry Department, Dr. Mahmoud Abdalrahman, Luke Fulton, Brady Barron, Matthew Reuter, Evangelos Rossis, and Dr. Roy Planalp.
Figure 3. 1H NMR of DFO coupled to Salicylic Acid
References
1. Leonard Fass; Imaging and cancer: A review. Molecular Oncology ,
2. Melissa A. Deri, Brian M. Zeglis, Lynn C. Francesconi, Jason S. Lewis; PET Imaging with 89Zr: From Radiochemistry to the Clinic. Nuclear Medicine and Biology
3. Francois Guerard, Yong-Sok Lee, Martin W. Brechbiel; Rational Design, Synthesis, and Evaluation of Tetrahydroxamic Acid Chelators for Stable Complexation of Zirconium(IV). Chemistry a European Journal. 2014, 20,
Figure 4. 1H NMR of DFO Mesylate