Preparation of an ¹⁸F‐Labeled Hydrocyanine Dye as a Multimodal Probe for Reactive Oxygen Species

Abstract

Hydrocyanine dyes are sensitive "turn-on" type optical probes that can detect reactive oxygen species (ROS). We have developed a method to prepare an F-labeled hydrocyanine dye as a multi-modal PET and optical "turn-on" probe. A commercially available near infrared (NIR) dye was modified with a fluorinated prosthetic group that did not alter its ROS sensing properties in the presence of superoxide and hydroxyl radicals. The F-labeled analogue was produced using a single-step terminal fluorination procedure. Positron emission tomography (PET) imaging and quantitative in vivo biodistribution studies indicated this novel probe had remarkably different pharmacokinetics compared to the oxidized cyanine analogue. The chemistry reported enables the use of quantitative and dynamic PET imaging for the in vivo study of hydrocyanine dyes as ROS probes.

Radiosynthesis of an 18F‐fluoroglycosylated aminoferrocene for in‐vivo imaging of reactive oxygen species activity by PET

“…These studies are promising, because the tracers showed ROS‐specific uptake in vitro and in vivo using an animal model of neuroinflammation. Moreover, Carroll et al reported a prodrug construct that releases the PET tracer 3′‐deoxy‐3′‐[ 18 F]fluorothymidine ([ 18 F]FLT) when reacting with ROS, and, more recently, a hydrocyanine dye has been reported allowing multimodal PET and optical imaging . However, the imaging of ROS activity in vivo in tumours has not yet been reported extensively.…”

Fluorine‐18 Radiolabelling and Photophysical Characteristics of Multimodal PET–Fluorescence Molecular Probes

“…Al‐Karmi, et al. also sought to radiofluorinate the Cy7 hydrocyanine dye, though for use as a PET coupled on‐off optical probe which would fluoresce in the presence of reactive oxygen species (ROS) [46] . An initial two‐step radiosynthesis of the compound involved nucleophilic aromatic substitution of a nitro‐substituted precursor ( 29 ) using [ 18 F]fluoride with a Kryptofix 222 phase transfer catalyst in DMF, followed by reduction of the iminium salt using sodium borohydride, as shown in Figure 15.…”

“… Cy7 dye with a 2‐[ 18 F]fluoropyridine prosthetic group for the PET imaging and on‐off optical sensing of ROS [46] . Initial syntheses starting from 29 involved a multistep radiofluorination and reduction reaction which afforded 31 in only 19 % RCY.…”

“…Al-Karmi, et al also soughtt or adiofluorinate the Cy7 hydrocyanine dye, thoughf or use as aP ET coupled on-off optical probe which would fluorescei nt he presence of reactive oxygen species( ROS). [46] An initial two-step radiosynthesis of the compound involved nucleophilic aromatic substitution of a nitro-substituted precursor (29)u sing [ 18 F]fluoride with aK ryptofix 222 phase transfer catalyst in DMF,f ollowedb yr eduction of the iminium salt using sodium borohydride,a ss hown in Figure 15. This approach afforded only 19 %R CY,h owever,a nd hence direct radiofluorination of the already reduced C7-Cy dye (30)w as instead trialled which afforded the desired tracer (31)i n6 2% RCY and with 5.2 GBq mmol À1 molar activity,t hus demonstrating the value of simplifying radiosyntheses to a single time-efficient radiofluorination step as to avoid any unnecessary loss of radioactivity.…”

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

“…[286] Weitere,auf ROS reagierende PET-Reagenzien haben Wilson, Va lliant et al verçffentlicht. [287,288] Renslo,E vans und Mitarbeiter synthetisierten PET-Sonden, um labile Eisenreservoirs in lebenden Tieren zu verfolgen, die bei der Bildgebung systemische Veränderungen der Eisenverfügbarkeit in spontanen Tu moren in Mäusen und in vivo aufdecken. Die Tu moren gehen auf ein molekularbiologisch etabliertes Prostatakrebsmodell durch den Verlust der Phosphatase PTEN (phosphatase and tensin homolog) zurück (Abbildung 7c).…”