In Vivo Evaluation of a Radiogallium-Labeled Bifunctional Radiopharmaceutical, Ga-DOTA-MN2, for Hypoxic Tumor Imaging

Abstract

On the basis of the findings obtained by X-ray crystallography of Ga-DOTA chelates and the drug design concept of bifunctional radiopharmaceuticals, we previously designed and synthesized a radiogalliumlabeled DOTA chelate containing two metronidazole moieties, 67Ga-DOTA-MN2, for hypoxic tumor imaging. As expected, 67Ga-DOTA-MN2 exhibited high in vivo stability, although two carboxyl groups in the DOTA skeleton were conjugated with metronidazole moieties. In this study, we evaluated 67/68 Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors. Key words radiogallium; bifunctional radiopharmaceutical; hypoxic tumor imaging; positron emission tomography Tumor hypoxia results from an imbalance between oxygen supply and consumption, which is caused by abnormal structure and function of microvessels supplying the tumor, increased diffusion distances between the nutritive blood vessels and the tumor cells, and reduced O 2 transport capacity of the blood.1,2) Tumor hypoxia has been associated with an aggressive tumor phenotype, poor response to radiotherapy and chemotherapy, and increased risk of invasion and metastasis of tumors.3,4) Thus, non-invasive measurement of tumor hypoxia with positron emission tomography (PET) would have a distinct effect on characterizing tumor malignancy and determining a course of therapy.Metronidazole, nitroimidazole antibiotic medication used for anaerobic bacteria and protozoa in particular, has a tendency to accumulate in the hypoxic regions and enhance the lethal effect of ionizing radiation for hypoxic tissues.5) The reduction of the nitroimidazole (RNO 2 ) within cells proceeds in successive steps involving enzyme-mediated electron transfer via the free radical anion (RNO

68Ga-DOTA and analogs: Current status and future perspectives

“…47 Copper-64 ATSM (diacetyl-bis(N4methylthiosemicarbazone) was indicated as an alternative, but suffers from less favorable dosimetry, associated with emission of ␤ − (38.5%), and solid target cyclotrone production ( 64 Ni(p,n) 64 Cu) which limits availability. Several 68 Ga-complexes with nitroimidazoles were proposed for hypoxic tumor imaging: DOTA-derivative with one or two metronidazole moieties, 48 imidazole coupled to DOTA by conjugating via an amide or thiourea bond. 49 The results obtained were comparable with reference images obtained with [ 18 F]FMISO and [ 18 F]FAZA, but the usage of methylated 5-nitroimidazole improved performance of 68 Ga-DOTA-nitroimidazoles in hypoxia imaging.…”

Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

“…These ratios were two-fold higher when compared to 67 Ga-DOTA, indicating the positive role of metronidazole in increased tumour uptake. PET images with 82 clearly delineated the implanted FM3A tumours, and autoradiography confirmed heterogeneous biodistribution within the tumours [96]. Ga-complexes in high radiochemical purity (>90%).…”

“…Based on promising preliminary animal studies with 83 [95], improved radiochemical yield (85%) and radiochemical purity (99%) were achieved using microwave-assisted reaction [96]. The effectiveness of the two metronidazole moieties in 83 was compared to the complex bearing only one metronidazole (84).…”

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

“…However derivatives of DOTA have improved upon this conjugation by using added linker side chains which will bind to the protein. By using X ray crystallography, it is possible to determine which functional groups are not significant in radiolabeled complexes [101]. One such example is the use of an amino acid-substituted BFC, DOTA-Phe-Ala, to bind to an anti EGFR mAb.…”