Radiosynthesis and Quality Assurance of 5-[ 124 I]Iodo-2'- deoxyuridine for Functional PET Imaging of Cell Proliferation Ilonka Guenther, 2 * Leo Wyer, 1 E. Joachim Knust, 3 Ronald D. Finn, 4 Jacek Koziorowski 1 and Regin Weinreich 1 1 INSTITUTE FOR MEDICAL RADIOBIOLOGY OF THE UNIVERSITY OF ZURICH AND THE PAUL SCHERRER INSTITUTE, CH-5232 VILLIGEN-PSI, SWITZERLAND; 2 PET PROGRAMME, PAUL SCHERRER INSTITUTE, CH-5232 VILLIGEN-PSI, SWITZERLAND; 3 NUCLEAR CHEMISTRY AND RADIOPHARMACY, CLINIC FOR NUCLEAR MEDICINE, UNIVERSITY HOSPITAL, D-45122 ESSEN, GERMANY; AND 4 RADIOCHEMISTRY AND CYCLOTRON CORE FACILITY, MEMORIAL SLOAN-KETTERING CANCER CENTER, NEW YORK, NEW YORK, USA ABSTRACT. 5-[ 124 I]Iodo-2-deoxyuridine ([ 124 I]IUdR) was routinely produced by direct electrophilic labelling of 2-deoxyuridine with 124 I of high specific activity (12 Ci/mol) in an Iodogen-coated ReactiVial, followed by purification on a Sep-Pak C-18 cartridge. The radiochemical purity was determined by TLC on a Silicagel-60 plate and by reverse-phase HPLC on a RP-18 column. Based upon 45 syntheses, the yield ranged from 45% to 65%. The radiochemical impurity of [ 124 I]IUdR was determined at 2.9% by TLC (mainly iodate) and 4.3% by HPLC. The chemical stability of the solvated formulation allowed a time window of 2 days following end of synthesis (EOS) for chemical application, based upon the required 95% radiochemical purity grade of [ 124 I]IUdR. The labelled compound was routinely used for the clinical determination of cell proliferation in glioma patients by positron emission tomography. NUCL MED BIOL 25;4: 359 –365, 1998. © 1998 Elsevier Science Inc. KEY WORDS. 5-[ 124 I]Iodo-2'-deoxyuridine, Radiolabelling, Quality assurance, Routine production, Cell proliferation, Positron emission tomography INTRODUCTION The ability to image cell proliferation functionally is an approach that could have significant impact for both the diagnosis and therapeutic intervention on a great variety of tumours. The corre- sponding radioactive tracer must be incorporated into the DNA, and therefore the measured radioactivity should indicate cell proliferation and tumour-associated alterations therein. To validate this approach, approximately 30 patients with known status of different brain tumours were investigated by positron emission tomography (PET) using 5-[ 124 I]Iodo-2'-deoxyuridine ([ 124 I]IUdR) as radioactive tracer (3). IUdR is an analog of thymidine, which has been used extensively to study the metabolic pathways of pyrimidine incorporation into DNA (18, 21). Thymi- dine has been previously labelled with 11 C (5) and has shown a large fraction of radiolabelled metabolites in PET measurements. However, the 20-min half-life proved to be too short to allow for sufficient tissue washout and body clearance of the non-bound tracer and its metabolites (24). A similar limitation seems to exist with attempts to measure uptake and retention of 18 F-labelled pyrimidines in tumours with PET, due to the 110-min physical half-life of 18 F (27). Four major reasons prompted our interest in the use of the novel tracer [ 124 I]IUdR for the measurement of cell proliferation: 1. Previous studies on animals and man demonstrated a substantial incorporation of inactive as well as radioactively labelled IUdR into the DNA of proliferating tissue 2 to 4 days after IV administration in animals (1, 13, 15, 20, 23, 25, 26). 2. Previous studies indicated that iodide is the major radiolabelled metabolite of [ 125 I]IUdR and [ 131 I]IUdR and that iodide shows a fast renal clearance from the human body when the thyroid was blocked for a time before administration (1, 6, 25). 1 3. The comparatively long physical half-lives of 131 I (8.1 days), 124 I (4.15 days), and possibly 123 I (13.2 h) are appropriate for the ‘‘washout’’ experiments carried out for visualization of cell proliferation in tumours (e.g., to image tumours when back- ground radioactivity is low and the dominant fraction of tumour radioactivity represents IUdR incorporated in DNA) (3, 25, 26). 4. Both 123 I and 131 I can be measured efficiently by single photon emission tomography (SPECT), and recent studies have demon- strated that the 124 I radioactivity can be measured accurately by PET in small volumes despite the large number of non-annihi- lation gamma emissions (3, 11, 22, 29). In most cases, radioiodinated deoxyuridine is produced by direct electrophilic iodination under attack of the COH bond in oxida- tive media. This method is normally carried out under various Address correspondence to: Regin Weinreich, Institute for Medical Radio- biology of the University of Zurich and the Paul Scherrer Institute, CH-5232 Villigen-PSI, Switzerland. * Present address: Service Hospitalier Fre ´de ´ric Joliot, CEA, 4 place du Ge ´ne ´ral Leclerq, F-91406 Orsay, France. Received 30 July 1997. Accepted 3 November 1997. 1 In the clinical trial referred in (3), the thyroid was blocked with Lugol solution (5% KI, Pharmacy of University Hospital Zurich, freshly prepared). The patients took 3  25 drops daily for 4 days, beginning 24 h before administration of [ 124 I]IUdR (U. Roelcke, PSI, private communication). Nuclear Medicine & Biology, Vol. 25, pp. 359 –365, 1998 ISSN 0969-8051/98/$19.00 + 0.00 Copyright © 1998 Elsevier Science Inc. PII S0969-8051(97)00220-5