Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography

Abstract

Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live animals. The responses of this reagent to systemic changes in labile iron disposition were revealed using iron supplementation and sequestration treatments in mice, while the potential of this approach for in vivo imaging of cancer was demonstrated using genetically and pathologically diverse mouse models, including spontaneous tumors arising in a genetically engineered model of prostate cancer driven by loss of PTEN.

In Vivo Imaging of the Tumor‐Associated Enzyme NCEH1 with a Covalent PET Probe

“…[12] Radiotracers that detect nutrient uptake, disease-associated protein conformation and abundance (e.g., Ab aggregates in Alzheimers disease), cell surface markers, metals, and other molecular features have been developed with the intention of clinical deployment. [13][14][15][16] Despite the longstanding use of PET in the clinic, there remains a need to identify new molecular targets and specific chemical probes for diagnostic imaging in disease. Toward this goal, we tested an emerging paradigm in radiotracer development by combining the selective targeting capacity of covalent activitybased probes [17] with the imaging power of PET to create an activity-based radiotracer targeting neutral cholesterol ester hydrolase 1 (NCEH1, also known as AADACL1 or KIAA1363).…”

Activity‐Based Sensing: A Synthetic Methods Approach for Selective Molecular Imaging and Beyond

“…These probes undergo an Fe II -dependent cleavage reaction to create asuite of ABS reagents for the detection of labile iron pools,including histochemical, [242] ratiometric, [243] bioluminescent, [244] and PET probes. [245] Lippard and co-workers exploited ad ual ABS/BBS approach by combining the Lewis acidity of zinc to hydrolyze an ester group to unveil af ree polypyridine receptor with ac oncomitant fluorescent turn-on response upon subsequent zinc binding. [246] Chan and co-workers utilized the Cu II -dependent cleavage of picolinic esters for the photoacoustic detection of copper.…”

Aktivitätsbasierte Sensorik: ein synthetisch‐methodischer Ansatz für die selektive molekulare Bildgebung und darüber hinaus.

“…Sie durchlaufen eine Fe II -abhängige Spaltung, bei der eine Reihe von ABS-geeigneten Reagentien zum Nachweis labiler Eisenreservoirs entstehen, darunter fürh istochemische, [242] ratiometrische, [243] Biolumineszenz- [244] und PET-Sonden. [245] In der Gruppe von Lippard wurde ein dualer ABS/BBS-Ansatz gewählt, indem durch die Lewis-Acidität von Zink eine Estergruppe hydrolysiert wird, um einen freien Polypyridinrezeptor freizulegen;z ugleich wird durch die nachfolgende Zinkbindung ein Fluoreszenzsignal erzeugt. [246] ¾hnliches ergab sich bei einer Untersuchung von Chan et al, die die Cu II -abhängige Spaltung von Picolinsäureestern zum photoakustischen Kupfernachweis nutzten.…”