Synthesis of I-131 labelled 4-iodophenylacetic acid Zoltan Szucs, a Mike Sathekge, b Biljana Marjanovic-Painter, a Judith Wagener, a Thato Sello, a Carl Wagener, a and Jan Rijn Zeevaart cà Phenylacetate has been reported to have a potent anti-proliferative and anti-differentiating effect in haematological malignancies and in solid tumours at non-toxic concentrations. This study is a preliminary investigation into the potential of 4-iodophenylacetic acid radiolabelled by 131 I as a radiopharmaceutical equivalent. The radiolabelling by isotope exchange gave a radiochemical yield of 5376%, and a radiochemical purity of 97.871.2% as qualified by HPLC. The product contained 4% ester by-product and is suitable for studies in animals. Keywords: biotracer; phenylacetic acid metabolism; prostate carcinoma; 131 I Introduction Phenylacetic acid (Figure 1) and its deprotonated form at physiological pH (phenylacetate) is an aromatic molecule and is present in low concentration in human serum as a product of phenylalanine metabolism. It is conjugated with glutamine in the liver by phenyl-acetyl coenzyme A to form phenyl-acetyl- glutamine, which is excreted in the urine. 1 Phenylacetate has been reported to have a potent anti- proliferative and anti-differentiating effect in haematological malignancies and in solid tumours at non-toxic concentrations. It has been used safely to treat children with inborn errors of urea synthesis and also in patients with hyperammonaemia. 1–3 Furthermore, it has been shown to inhibit tumor growth while sparing normal tissue and to induce phenotypic reversion and differentiation of malignant cells with some of the antiprolifera- tive effect of phenyl-acetate in prostate carcinoma, 4 melanoma, 5 rhabdomyosarcoma, 6 breast cancer, 7 pancreatic adenocarcino- ma, 8,9 ovarian carcinoma, 9 B-chronic lymphocytic leukemia 10 and medullablastoma 11 cell lines. In patients with hormone-refractory prostate cancer and high- grade glioma, Phase I trials of phenylacetate showed minimal toxicity, and a partial response was observed at a serum concentration of 2–10  10 3 M. 12,13 Increasing evidence points to phenylacetate having multiple effects on gene expression and on regulatory proteins responsible for its antineoplastic effects. 14 Thus, phenylacetate has been shown to down-regulate Bcl-2 and up-regulate bax/ p21 apoptosis-related genes in ovarian carcinoma cells and up- regulate p21 in K-ras mutant MCF-7 ras breast cancer cell lines. 9,15 Phenylacetate also activates the human peroxisome proliferator-activated receptors (PPAR) which belong to the superfamily of nuclear steroid receptors such as retinoids, vitamin D, and thyroid hormone receptors – all important regulators of cell growth and differentiation. 16,17 In all these studies phenylacetate exerts its effects at clinically acceptable serum concentration levels (2.5–10  10 3 M). 14 In recent years, the quest for an agent that can be used for both the diagnosis and therapy of a disease is being addressed world-wide. Most notable is the application of the synergism between the chemistry of the isotopes of technetium ( 99m Tc) and rhenium ( 186 Re and 188 Re), in which the former isotope is used for diagnosis and the latter for therapy of the disease. 18,19 131 I-labelled compounds fulfil the criteria of being both a diagnostic and/or therapeutic agent. Although the g-energy of 131 I is not ideal (t 1/2 = 8.02 d; g-energy = 364 keV; b-energy = 0.610.8 MeV, 19 it is adequate for use in diagnostic studies using a high-energy CH 2 COOH H C COOH NH 2 CH 2 COOH I CH 2 COOEt I 4-iodophenylacetic acid Phenylalanine Phenylacetic acid Ethyl 2-(4-iodophenyl)acetate Figure 1. The structures of 4-iodophenylacetic acid, phenylacetic acid, phenyla- lanine and ethyl 2-(4-iodophenyl)acetate. a Necsa, Radiochemistry, Pretoria, South Africa b University of Pretoria/Pretoria Academic Hospital Pretoria, Pretoria, South Africa c CARST, North West University, Mafikeng Campus, PO Box 582, Pretoria 0001, Mmabatho, South Africa *Correspondence to: Jan Rijn Zeevaart, CARST, PO Box 582, Pretoria 0001, South Africa. E-mail: janrijn.zeevaart@necsa.co.za Research Article Received 19 January 2010, Revised 6 May 2010, Accepted 3 June 2010 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jlcr.1812 J. Label Compd. Radiopharm 2010 Copyright r 2010 John Wiley & Sons, Ltd.