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Pharmaceuticals 2019, 12(1), 3; https://doi.org/10.3390/ph12010003

Development of [131I]I-EOE-TPZ and [131I]I-EOE-TPZMO: Novel Tirapazamine (TPZ)-Based Radioiodinated Pharmaceuticals for Application in Theranostic Management of Hypoxia

1
Department of Oncology, Cross Cancer Institute, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, El Sultan Hussein St. Azarita, Alexandria 21521, Egypt
3
Current address: Centre for Probe Development and Commercialization, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada
4
Joint Appointment to Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
*
Author to whom correspondence should be addressed.
Received: 29 November 2018 / Revised: 18 December 2018 / Accepted: 20 December 2018 / Published: 1 January 2019
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Abstract

Introduction: Benzotriazine-1,4-dioxides (BTDOs) such as tirapazamine (TPZ) and its derivatives act as radiosensitizers of hypoxic tissues. The benzotriazine-1-monoxide (BTMO) metabolite (SR 4317, TPZMO) of TPZ also has radiosensitizing properties, and via unknown mechanisms, is a potent enhancer of the radiosensitizing effects of TPZ. Unlike their 2-nitroimidazole radiosensitizer counterparts, radiolabeled benzotriazine oxides have not been used as radiopharmaceuticals for diagnostic imaging or molecular radiotherapy (MRT) of hypoxia. The radioiodination chemistry for preparing model radioiodinated BTDOs and BTMOs is now reported. Hypothesis: Radioiodinated 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ), a novel bioisosteric analogue of TPZ, and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide (I-EOE-TPZMO), its monoxide analogue, are candidates for in vivo and in vitro investigations of biochemical mechanisms in pathologies that develop hypoxic microenvironments. In theory, both radiotracers can be prepared from the same precursors. Methods: Radioiodination procedures were based on classical nucleophilic [131I]iodide substitution on Tos-EOE-TPZ (P1) and by [131I]iodide exchange on I-EOE-TPZ (P2). Reaction parameters, including temperature, reaction time, solvent and the influence of pivalic acid on products’ formation and the corresponding radiochemical yields (RCY) were investigated. Results: The [131I]iodide labeling reactions invariably led to the synthesis of both products, but with careful manipulation of conditions the preferred product could be recovered as the major product. Radioiodide exchange on P2 in ACN at 80 ± 5 °C for 30 min afforded the highest RCY, 89%, of [131I]I-EOE-TPZ, which upon solid phase purification on an alumina cartridge gave 60% yield of the product with over 97% of radiochemical purity. Similarly, radioiodide exchange on P2 in ACN at 50 ± 5 °C for 30 min with pivalic acid afforded the highest yield, 92%, of [131I]I-EOE-TPZMO exclusively with no trace of [131I]I-EOE-TPZ. In both cases, extended reaction times and/or elevated temperatures resulted in the formation of at least two additional radioactive reaction products. Conclusions: Radioiodination of P1 and P2 with [131I]iodide leads to the facile formation of [131I]I-EOE-TPZMO. At 80 °C and short reaction times, the facile reduction of the N-4-oxide moiety was minimized to afford acceptable radiochemical yields of [131I]I-EOE-TPZ from either precursor. Regeneration of [131I]I-EOE-TPZ from [131I]I-EOE-TPZMO is impractical after reaction work-up. View Full-Text
Keywords: hypoxia; radiosensitizer; benzotriazine-1,4-dioxide (BTDO), benzotriazine-1-monoxide (BTMO), tirapazamine (TPZ), SR 4317; radioiodination hypoxia; radiosensitizer; benzotriazine-1,4-dioxide (BTDO), benzotriazine-1-monoxide (BTMO), tirapazamine (TPZ), SR 4317; radioiodination
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Elsaidi, H.; Ahmadi, F.; Wiebe, L.I.; Kumar, P. Development of [131I]I-EOE-TPZ and [131I]I-EOE-TPZMO: Novel Tirapazamine (TPZ)-Based Radioiodinated Pharmaceuticals for Application in Theranostic Management of Hypoxia. Pharmaceuticals 2019, 12, 3.

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