Radiolabelling and evaluation of a novel sulfoxide as a PET imaging agent for tumor hypoxia.
[¹⁸F]FMISO is the most widely validated PET radiotracer for imaging hypoxic tissue. However, as a result of the pharmacokinetics of [¹⁸F]FMISO a 2h wait between tracer administration and patient scanning is required for optimal image acquisition. In order to develop hypoxia imaging agents with faster kinetics, we have synthesised and evaluated several F-18 labelled anilino sulfoxides. In this manuscript we report on the synthesis, in vitro and in vivo evaluation of a novel fluoroethyltriazolyl propargyl anilino sulfoxide. The radiolabelling of the novel tracer was achieved via 2-[¹⁸F]fluoroethyl azide click chemistry. Radiochemical yields were 23 ± 4% based on 2-[¹⁸F]fluoroethyl azide and 7 ± 2% based on K[¹⁸F]F. The radiotracer did not undergo metabolism or defluorination in an in vitro assay using S9 liver fractions. Imaging studies using SK-RC-52 tumors in BALB/c nude mice have indicated that the tracer may have a higher pO₂ threshold than [¹⁸F]FMISO for uptake in hypoxic tumors. Although clearance from muscle was faster than [¹⁸F]FMISO, uptake in hypoxic tumors was slower. The average tumor to muscle ratio at 2h post injection in large, hypoxic tumors with a volume greater than 686 mm³ was 1.7, which was similar to the observed ratio of 1.75 for [¹⁸F]FMISO. Although the new tracer showed improved pharmacokinetics when compared with the previously synthesised sulfoxides, further modifications to the chemical structure need to be made in order to offer significant in vivo imaging advantages over [¹⁸F]FMISO.
School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville VIC 3052, Australia.
Evelyn
E
Laurens
Centre for PET, Austin Health, Level 1 HSB, 145 Studley Road, Heidelberg VIC 3084, Australia.
Shinn Dee
SD
Yeoh
Ludwig Institute for Cancer Research, Melbourne - Austin Branch, Heidelberg VIC 3084, Australia.
Angela
A
Rigopoulos
Ludwig Institute for Cancer Research, Melbourne - Austin Branch, Heidelberg VIC 3084, Australia.
Diana
D
Cao
Ludwig Institute for Cancer Research, Melbourne - Austin Branch, Heidelberg VIC 3084, Australia.
Glenn A
GA
Cartwright
Centre for PET, Austin Health, Level 1 HSB, 145 Studley Road, Heidelberg VIC 3084, Australia.
Graeme J
GJ
O'Keefe
Centre for PET, Austin Health, Level 1 HSB, 145 Studley Road, Heidelberg VIC 3084, Australia; School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne VIC 3010, Australia.
Henri J
HJ
Tochon-Danguy
School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville VIC 3052, Australia.
Jonathan M
JM
White
Centre for PET, Austin Health, Level 1 HSB, 145 Studley Road, Heidelberg VIC 3084, Australia; Ludwig Institute for Cancer Research, Melbourne - Austin Branch, Heidelberg VIC 3084, Australia; School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne VIC 3010, Australia.
Andrew M
AM
Scott
Centre for PET, Austin Health, Level 1 HSB, 145 Studley Road, Heidelberg VIC 3084, Australia; Ludwig Institute for Cancer Research, Melbourne - Austin Branch, Heidelberg VIC 3084, Australia; School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne VIC 3010, Australia. Electronic address: uwea@unimelb.edu.au.
Uwe
U
Ackermann
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D007680:Kidney Neoplasms / Q000473:pathology*; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D013454:Sulfoxides / Q000737:chemistry / Q000493:pharmacokinetics
D013454:Sulfoxides
Click chemistry; Hypoxia; LCMS; Radiolabelling; Radiotracer metabolism; SK-RC-52 tumor model