Conjugates and their use as imaging agents

Abstract

The invention relates to compounds according to Formula (I) wherein A is —As(OH)2 or an arsenoxide equivalent group; each of R1, R2, R3 and R4 is independently selected from H, X, OH, NH2, CO, SCN, —CH2NH, —NHCOCH3, —NHCOCH2X or NO, and X is a halogen; R5 is —NHCH2COOH, OH or OR6, wherein R6 is a C1-5 straight or branched alkyl group; and Z is a radioisotope with a half-life of less than 4 days, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, uses of said compounds, and methods of preparing said compounds. The invention also relates to diagnostic methods utilizing said compounds.

Description

TECHNICAL FIELD[0001]The present invention broadly relates to a radiolabelled conjugate according to Formula (I) defined herein, and a compound according to Formula (II) defined herein. The present invention further relates to the use of such radiolabelled conjugates in imaging of cell death, diagnosis and treatment of conditions associated with cell death, and methods of producing such radiolabelled conjugates.BACKGROUND OF THE INVENTION[0002]Cell death plays an integral role in cell turnover. An imbalance of cell death, characterised by a marked increase or decrease of cell death relative to cell regeneration, is often associated with disease. For example, excessive cell death is characteristic of vascular disorders, neurodegenerative diseases, myelodysplastic syndromes, ischaemia / reperfusion injury, organ transplant rejection, and neoplastic conditions including tumours and cancers, among others. In particular, cancer results from imbalance between rates of cellular proliferation...

AI Technical Summary

Benefits of technology

This patent describes compounds that can be used to image cell death in humans. These compounds are advantageous because they are sensitive and non-invasive, allowing for accurate detection and measurement of cell death. They can be easily synthesised and have good imaging characteristics, allowing for frequent and repeated imaging. The compounds are particularly useful for diagnosing, monitoring, and assessing treatment of conditions associated with changes in cell death, such as neoplastic or autoimmune diseases. The use of a short-lived positron emitting radioisotope allows for frequent and quantitative imaging, and multiple imaging sessions may be needed to gather more accurate and quantitative assessments of cell death. Overall, the compounds described in this patent offer a valuable tool for studying cell death in humans and have potential to improve the diagnosis, monitoring, and treatment of conditions associated with cell death.

Problems solved by technology

In particular, cancer results from imbalance between rates of cellular proliferation and survival in a tissue.

Although these techniques are widely and routinely used in oncology, they indirectly assess cell death, and are thus subject to both false positive and false negative findings.

In addition, these techniques do not assess cell death in real time and typically are not performed until at least a number of weeks after commencement of therapy (e.g. positron emission tomography with 2-fluoro-2-deoxyglucose (FDG PET / CT) is usually not performed until after two cycles of chemotherapy—typically 6 to 8 weeks after commencement of treatment).

Reduction in tumour size is slow to occur following commencement of treatment (often taking several months) and in some cases may not occur at all despite a response to therapy.

Limited attempts have been made to directly image cell death, such as using derivatives of Annexin V and radiolabelled caspase 3 / 7 inhibitors, however these have been hampered by complex and expensive production, poor biodistribution, particularly with high physiologic uptake in blood and normal tissues / organs, especially the liver and bowel, poor tissue penetration and an inability to reliably detect tumour cell death in response to treatment.

In view of the absence of methods to reliably detect tumour cell death in response to therapy in vivo, the kinetics of cell death are poorly understood.

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