4-[18F]Fluoroiodobenzene and its applications in palladium-mediated Sonogashira cross coupling reactions

  • Author / Creator
    Way, Jenilee D
  • Way, Jenilee1; Wang, Monica1; Wuest, Melinda1; Bergmann, Cody1; Hamann, Ingrit1; Wuest, Frank1* 1 University of Alberta, Department of Oncology, Edmonton, Alberta, Canada The ongoing demand for novel 18F-labelled radiotracers is frequently accompanied with the need to develop novel radiolabelling techniques. Synthesizing radiotracers should preferentially involve rapid, selective and functional group-tolerating reactions. In this line, the use of catalysts such as enzymes or transition metal complexes has proved to be particularly valuable for rapid and efficient syntheses of a wide variety of 18F-radiolabelled compounds. Here we present a four-chapter Masters thesis: Chapter 2 starts with a review of palladium-mediated cross-coupling reactions in radiochemistry1. Showing the utility and versatility of various Pd-mediated chemical reactions as applicable to the synthesis of radiolabelled PET imaging probes. From this review we will be focusing on the use of the Sonogashira reaction, which involves the reaction between 4-[18F]fluoroiodobenzene ([18F]FIB) along with a terminal alkyne in order to create a new carbon-carbon bond. Chapter 3 outlines the use [18F]FIB in the Sonogashira cross-coupling reaction as it provides the ability to produce large amounts of this prosthetic group in a reliable and robust manner. In line with this, we created a fully automated synthesis of [18F]FIB2, achieving 89 ± 10 % (n=7) decay-corrected radiochemical yields within a reaction time of 59 ± 2 min including HPLC purification. Allowing for up to 6.4 GBq of [18F]FIB to be produced from 10.4 GBq of n.c.a. [18F]fluoride, with a radiochemical purity greater than 97 % and a specific activity greater than 40 GBq/μmol. In chapter 4, we demonstrate the applicability of the Sonogashira cross-coupling reaction using ASU produced [18F]FIB to a simple amino acid of propargylglycine in order to produce the novel 18F-labelled amino acid radiotracer of 2-amino-5-(4-[18F]fluorophenyl)pent-4-ynoic acid ([18F]FPhPA)3. This C-C bond forming reaction is optimized in terms of the Pd-complexes, solvents, reaction temperatures, reaction times and amounts of propargylglycine and triethylamine used. After complete optimization and HPLC purification [18F]FPhPA could be obtained in 42 ± 10% (n=11) decay-corrected radiochemical yields within 56 ± 5 min based on 4-[18F]fluoroiodobenzene. Overall 480 MBq of D/L-[18F]FPhPA could be isolated in high radiochemical purity of greater 95% starting from 1200 MBq of 4-[18F]fluoroiodobenzene. [18F]FPhPA was also analyzed in both in vivo and in vitro with EMT6 cells, as compared to the current clinical standard amino acid radiotracer of [18F]FET. Overall as a PET imaging agent L-[18F]FPhPA gave a maximum standardized uptake value (SUV) of 1.35 after 60 min p.i. which was higher than that of the comparable L-[18F]FET (SUV60min 1.22) in BALB/c mice bearing subcutaneous EMT6 tumors. Finally, chapter 5 illustrates the expanded application of this methodology from a single acid to a larger 9 amino acid peptide as the Sonogashira reaction with [18F]FIB is further tested in terms of applicability to biomolecules. Here the reaction of [18F]FIB with a model bombesin peptide, is tested in terms of Pd-complexes, solvents, reaction temperatures, reaction times, and peptide concentration. After complete optimization [18F]FBpBBN could be achieved with a 71 ± 4% radiochemical yield after a 35 min reaction time, including HPLC purification. The specific activity of [18F]FBpBBN was calculated to be 625 ± 334 GBq/μmol (n=3). Overall showing the utility of this method in radiolabelling a biological molecules of interest, as optimized this reaction proceeds at room temperature in as little as 10 minutes. Overall, an innovative and useful method is demonstrated which can lead to the 18F-radiolabelling of biomolecules using aqueous reaction conditions with a palladium mediated cross-coupling reaction. References: [1] Way et al. Curr. Org. Chem., 2013, 17, 2138-2152. [2] Way et al. J. Labelled Compds. Radiopharm., 2014, 57, 104-109. [3] Way et al. Nucl. Med Biol., 2014, 41, 660-669.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Oncology
  • Specialization
    • Experimental Oncology
  • Supervisor / co-supervisor and their department(s)
    • Wuest, Frank (Oncology)
  • Examining committee members and their departments
    • Velazquez, Carlos (Pharmacy)
    • Wilson, John (Oncology)
    • Schirrmacher, Ralf (External, Montreal Neurological Institute)