Abstract View
High Molar Activity [131I]iodophenylalanine via DoE Optimization of Radioiododeborylation
Category: Other Halogen Radionuclide Chemistry
Authors:
Yngve Guttormsen1, Hong Beom Lee1, Anna Kulesza2, Daniel Yokell2, Michael Veronesi3, Paul Ellison1
1Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
2Telix Pharmaceuticals Limited. 55 Flemington Road, North Melbourne, VIC 3051, Australia.
3Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Objectives: [131I]Iodophenylalanine (Iodofalan (131I), [131I]1) leverages the large neutral amino acid transporter-1 (LAT1) to be transported into glioma cells and is currently being investigated in a phase 3 clinical trial for glioblastoma treatment1. The Iodofalan (131I) used in these trials has low molar activity typical of carrier-added (c.a.) production via isotope exchange2. Here we present development of no-carrier added (n.c.a.) radiopharmaceutical synthesis methodologies for Iodofalan (131I) via radioiododeborylation, employing a design of experiment (DoE) approach to optimize the labeling process for preclinical investigations.
Methods: Boronophenylalanine (BPA, 2) and its protected derivatives were evaluated as precursors for iodine-131 labeling. Investigated oxidative methods used N-bromosuccinamide (NBS), peracetic acid, and Chloramine-T (CAT), while copper-mediated methods utilized Cu(py)4(OTf)2 and 3,4,7,8-tetramethyl-1,10-phenanthroline. The deprotection of labeled precursors was performed with HCl, sodium ascorbate, and heat. DoE was performed using the MODDE (v13.1) software from Sartorius using a D-optimal screening design with linear and quadratic terms. In total, 13 experiments were performed exploring six factors, all on the same day.
Results: Oxidative iodine-131 labeling of BPA yielded maximum radiochemical conversions (RCC) of 30% with NBS, 20% with peracetic acid, and 51% with CAT. Copper-mediated labeling using standard conditions3 gave RCCs of 0% (n = 4) (for precursor 2), 62±8% (n = 3) (N-Boc protected BPA, 3), and 97±2% (n = 15) (N-Boc, O-tBu protected BPA, 4). DoE optimization of copper-mediated iodine-131 labeling of N-Boc BPA 3 gave a response surface model (Figure 1B). Implementing the optimal conditions from the response surface model increased the RCC from 62±8% to 99±0% (n = 4, figure 1A). More than 99% Boc deprotection was achieved with heating in aqueous HCl. Addition of ascorbate reduced the copper(II) avoiding its complexation with [131I]1 and establishing a robust method for semi-preparative high performance liquid chromatography (HPLC) purification. Following HPLC and cartridge-based reformulation, the overall activity yield was 61±10% (n = 4) with a molar activity of 72±14 GBq/µmol (n = 4), representing approximately a 1000-fold increase over the GBq/mmol range typical of c.a. production.
Conclusions: We show the utility of DoE optimization for increasing radiochemical conversion of precursors with poorly tolerated functional groups, applied to the synthesis of Iodofalan (131I) for preclinical use. We show the necessity of removing copper before HPLC purification and present a synthesis amenable to automatization.
Acknowledgements: This work was funded as a sponsored research project by Telix Pharmaceuticals.
References:
[1] IPAX BrIGHT. ClinicalTrials.gov identifier: NCT07100730.
[2] Farah K et al. J Label Compd Radiopharm. 1997;39(11):915-926.
[3] Reilly SW et al. Org Lett. 2018;20(7):1752-1755.
