Synthesis of 2-[(4-[ 18 F]Fluorobenzoyloxy) methyl]-1,4-naphthalenedione from 2-hydroxymethyl 1,4-naphthoquinone and 4-[ 18 F]fluorobenzoic acid using dicyclohexyl carbodiimide Uwe Ackermann, a,b * Duanne Sigmund, a,d Shinn Dee Yeoh, a Angela Rigopoulos, c Graeme O’Keefe, a,b Glenn Cartwright, c Jonathan White, d Andrew M. Scott, a,b,c and Henri J. Tochon-Danguy a,b 2-[(4-[ 18 F]Fluorobenzoyloxy)methyl]-1,4-naphthalenedione ([ 18 F] 1) was synthesised as a putative hypoxia imaging agent from 2-hydroxymethyl 1,4-naphthoquinone ( 7) and 4-[ 18 F]fluorobenzoic acid ([ 18 F] 8) using dicyclohexyl carbodiimide (DCC) to activate [ 18 F] 8. This coupling reaction was fast and gave quantitative yields. Further investigations are warranted on the use of DCC as a coupling agent in Positron Emission Tomography. The synthesis including HPLC purification and reformulation has been fully automated on a modified FDG synthesiser with two reactor vials. [ 18 F] 1 was produced in a radiochemical yield of 27  5%, with a radiochemical purity of 97.5% and a specific activity of 78.4–134.5 GBq/mmol at the end of synthesis (n = 23). The total synthesis time including reformulation was 65 min. [ 18 F] 1 was found to be stable in plasma and saline, but underwent rapid metabolism in a phase 1 metabolite assay using rat S9 liver fractions. An in vivo evaluation of [ 18 F] 1 in transplanted, hypoxic SK-RC-52 tumour-bearing BALB/c nude mice revealed the tumour-to-muscle ratio to be 2.4  0.1 at 2 h post-injection. Keywords: fluorine-18; PET chemistry; 4-fluorobenzoate; tumor hypoxia; DCC; SK-RC-52 tumors Introduction Imaging of hypoxic tissue is of great significance in oncology because hypoxic tumours are more resistant to radiotherapy and chemotherapy than normoxic tumours. 1 For the planning of cancer therapy, the measurement of the hypoxic fraction of tumours is therefore of critical importance. 2,3 The gold standard for the measurement of oxygen partial pressure (pO 2 ) is by using a polarographic oxygen electrode. 4 Unfortunately, this is an invasive technique and therefore is not suitable for routine clinical application. Positron Emission Tomo- graphy (PET) is noninvasive and offers the potential to measure physiological processes in vivo. To date, the most commonly used radiotracers for PET imaging of tumour hypoxia are the nitroimidazole-based compounds [ 18 F]FMISO and [ 18 F]FAZA. 5,6 However, slow accumulation in hypoxic tissue and slow clearance from normoxic tissue result in a low target-to-background ratio and a 2 h delay between tracer administration and actual scan- ning of the patient. Also, [ 18 F]FMISO only shows uptake in tumours with a pO 2 value below 10 mm Hg, and a differential assessment of tumour hypoxia is therefore not possible. These shortcomings of the existing tracers have sparked the develop- ment of new tracers for hypoxia imaging. Most novel tracers reported in the literature have retained the 2-nitroimidazole core as the biologically relevant moiety responsible for the trapping in the hypoxic cell. 7–9 However, in our laboratory we have synthe- sised two fluorine-18-labelled haloethyl sulfoxides, which we have investigated in vivo and in vitro as a new class of hypoxia imaging agents. 10 Although these compounds showed great promise in the imaging of hypoxic tissue in a middle cerebral artery occlusion stroke model in rats, the clinical use of these compounds was deemed unsuitable because their structure is closely related to that of highly toxic nitrogen mustards. In our search for potential novel hypoxia imaging agents, we have found in the literature that derivatives of 2-hydroxymethyl a Centre for PET, Austin Health, Melbourne, Australia b The University of Melbourne, School of Medicine, Dentistry and Health Sciences, Melbourne, Australia c Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, Australia d The University of Melbourne, Bio21 Institute, Melbourne, Australia *Correspondence to: Uwe Ackermann, Centre for PET, Austin Health, Melbourne, Australia. E-mail: ackerman@petnm.unimelb.edu.au Copyright © 2011 John Wiley & Sons, Ltd. J. Label Compd. Radiopharm 2011, 54 788–794 Research Article Received 8 June 2011, Revised 10 August 2011, Accepted 17 August 2011 Published online 23 September 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jlcr.1932 788