Nitroimidazole-Containing H2dedpa and H2CHXdedpa Derivatives as Potential PET Imaging Agents of Hypoxia with (68)Ga.
(68)Ga is an attractive radiometal for use in positron emission tomography (PET) imaging. The success of (68)Ga-based agents is dependent on a chelator that exhibits rapid radiometal incorporation, and strong kinetic inertness to prevent transchelation of (68)Ga in vivo. The linear chelating agents H2dedpa (1,2-[[6-carboxypyridin-2-yl]methylamino]ethane) and H2CHXdedpa (CHX = cyclohexyl/cyclohexane) (N4O2) have recently been developed that bind Ga(3+) quickly and under mild conditions, ideal properties to be incorporated into a (68)Ga PET imaging agent. Herein, nitroimidazole (NI) derivatives of H2dedpa and H2CHXdedpa to investigate specific targeting of hypoxic tumor cells are investigated, given that NI can be reduced and retained exclusively in hypoxic cells. Nine N,N'-bis-alkylated derivatives of H2dedpa and H2CHXdedpa have been synthesized; they have been screened for their ability to bind gallium, and cyclic voltammetry of nonradioactive complexes was performed to probe the redox cycling mechanism of NI. The compounds were radiolabeled with (67)Ga and (68)Ga and show promising radiolabeling efficiencies (>99%) when labeled at 10(-5) M for 10 min at room temperature. Moreover, stability studies (via apo-transferrin challenge, 37 °C) show that the (67)Ga complexes exhibit exceptional stability (86-99% intact) after 2 h. In vitro uptake studies under hypoxic (0.5% O2) and normoxic (21% O2) conditions in three cancerous cell lines [HT-29 (colon), LCC6(HER-2) (breast), and CHO (Chinese hamster ovarian)] were performed. Of the four H2dedpa or H2CHXdedpa NI derivatives tested, all showed preferential uptake in hypoxic cells compared to normoxic cells with hypoxic/normoxic ratios as high as 7.9 ± 2.7 after 120 min. The results suggest that these novel bis-alkylated NI-containing H2dedpa and H2CHXdedpa ligands would be ideal candidates for further testing in vivo for PET imaging of hypoxia with (68)Ga.
†Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.|‡TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Caterina F
CF
Ramogida
§BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
Jinhe
J
Pan
∥Nordion, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Cara L
CL
Ferreira
†Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Brian O
BO
Patrick
†Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Karla
K
Rebullar
§BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
Donald T T
DT
Yapp
§BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
Kuo-Shyan
KS
Lin
‡TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Michael J
MJ
Adam
†Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Chris
C
Orvig
D000818:Animals; D016466:CHO Cells; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D003412:Cricetulus; D005021:Ethylamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005710:Gallium Radioisotopes / Q000737:chemistry*; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D009593:Nitroimidazoles / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D003287:Contrast Media; D056831:Coordination Complexes; D005021:Ethylamines; D005710:Gallium Radioisotopes; D008024:Ligands; C000596869:N,N'-((6-carboxylato)pyridin-2-yl)methyl)-1,2-diaminoethane; D009593:Nitroimidazoles; D011725:Pyridines; D019275:Radiopharmaceuticals