Non‐invasive MRS in new anticancer drug development

Abstract

In the rational development of anticancer drugs it is important to employ all the available pharmacological information. Early clinical trials provide an opportunity for hypothesis testing. MRS techniques have the potential to provide valuable data on the preclinical and clinical pharmacokinetics and pharmacodynamics of drugs non-invasively. Here we illustrate advantages and pitfalls of MRS using studies of two fluorine-containing cancer drugs: a beta,beta-difluoro analogue of the alkylating agent chlorambucil and a fluorinated derivative of the nitroimidazole misonidazole, Ro 07-0741. Limitations include signal quenching via protein binding and inadequate sensitivity for more potent drugs like beta,beta-difluorochlorambucil; but fluoromisonidazole was shown to accumulate in tumours and shows promise as a chemical probe for tumour hypoxia, detectable by 19F MRS.

19F: A Versatile Reporter for Non-Invasive Physiology and Pharmacology Using Magnetic Resonance

“…By attaching a fluorine label to the nitroimidazole, it has become possible to detect the presence of hypoxic cells using in vivo NMR techniques [150]. Studies have reported the fluorinated nitroimidazoles CCI-103F [248][249][250][251][252], Ro 07-0741 [249,253] and SR-4554 [254][255][256][257][258][259], which contain 6, 1 and 3 fluorine atoms per molecule, respectively ( Table 7). Subsequent to administration, a washout period sufficient for elimination of unbound marker is required, since there is apparently no difference detectable in vivo in the chemical shifts of the parent molecule and the metabolites [150].…”

MRI & MRS assessment of the role of the tumour microenvironment in response to therapy

“…Nitroimidazole compounds undergo bioreductive metabolism in hypoxia and bind to tissue macromolecules. Various fluorinated nitroimidazoles used for the detection of hypoxia by 19 F MRS/MRI are discussed below.…”

VatuximabTM: Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

“…Fluorine-19 labels have been introduced into the nitroimidazole structure providing NMR-sensitive agents [351,352]. Studies have reported the fluorinated nitroimidazoles CCI-103F [353], Ro 07-0741 [354], and SR4554 [351,355,356], which contain 6, 1, and 3 fluorine atoms per molecule, respectively (Table 6). Subsequent to administration, a washout period sufficient for elimination of unbound marker is required, since there is apparently no difference detectable in vivo in the chemical shifts of the parent molecule and the metabolites [351].…”