Synthesis and in Vivo Biological Evaluation of (68)Ga-Labeled Carbonic Anhydrase IX Targeting Small Molecules for Positron Emission Tomography.
Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, [(68)Ga]-2, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing (68)Ga for preclinical CA IX imaging are scarce, and this is one of the first effective (68)Ga compounds reported for PET imaging of CA IX.
Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Deborah
D
Sneddon
Maastricht Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University , Medical Centre, 6200 MD Maastricht, The Netherlands.
Raymon
R
Niemans
Departments of Radiology and Nuclear Medicine, Maastricht University Medical Centre , 6202 AZ Maastricht, The Netherlands.
Matthias
M
Bauwens
Maastricht Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University , Medical Centre, 6200 MD Maastricht, The Netherlands.
Ala
A
Yaromina
Maastricht Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University , Medical Centre, 6200 MD Maastricht, The Netherlands.
Simon J A
SJ
van Kuijk
Maastricht Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University , Medical Centre, 6200 MD Maastricht, The Netherlands.
Natasja G
NG
Lieuwes
Maastricht Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University , Medical Centre, 6200 MD Maastricht, The Netherlands.
Rianne
R
Biemans
Departments of Radiology and Nuclear Medicine, Maastricht University Medical Centre , 6202 AZ Maastricht, The Netherlands.
Ivo
I
Pooters
LifeSciences Division, Australian Nuclear Science and Technology Organisation (ANSTO), Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
Paul A
PA
Pellegrini
LifeSciences Division, Australian Nuclear Science and Technology Organisation (ANSTO), Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
Nigel A
NA
Lengkeek
LifeSciences Division, Australian Nuclear Science and Technology Organisation (ANSTO), Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
Ivan
I
Greguric
Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Kathryn F
KF
Tonissen
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Università degli Studi di Firenze , 50019 Sesto Fiorentino, Italy.
Claudiu T
CT
Supuran
Maastricht Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University , Medical Centre, 6200 MD Maastricht, The Netherlands.
Philippe
P
Lambin
Maastricht Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University , Medical Centre, 6200 MD Maastricht, The Netherlands.
Ludwig
L
Dubois
Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Sally-Ann
SA
Poulsen
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX / Q000032:analysis* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005710:Gallium Radioisotopes; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D005710:Gallium Radioisotopes; D054852:Small Molecule Libraries; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX