Abstract
1561
Objectives Carbonic anhydrase IX (CA IX) is upregulated in cancer cells in response to the hypoxic tumor microenvironment making it an important molecular target for radiopharmaceutical development. A series of small molecule CA IX inhibitors containing Re were synthesized and evaluated for selective inhibition of CA IX.
Methods CA IX inhibitors were synthesized that incorporated a benzenesulfonamide (BnS), indanesulfonamide (IdS) or indolesulfonamide (IoS) targeting moiety tethered via a variety of linkers to chelators of Re/Tc. As a preliminary screen, compounds were tested for CA IX dependent inhibition of 4-nitrophenylacetate hydrolysis at 1 µM. Active Re compounds were further screened at 1-10,000 nM to obtain IC50 values for inhibition of CA IX and CA II.
Results BnS analogs showed potent activity and selectivity for CA IX while IdS and IoS analogs generally showed weak activity. A linker attached to BnS via a thiourea moiety provided higher activity than via an amide group. The overall linker length did not affect the activity of the compounds; extension of the linker away from the BnS ring revealed that no spacer resulted in higher activity than a methylene or ethylene spacer. Incorporation of PEG or EDTA in the linker to improve solubility and reduce cellular permeability ablated activity.
Conclusions Several Re compounds showed excellent selectivity for CA IX over CA II with low nM IC50 values. The most active compounds were radiolabeled with Tc-99m in high yield and purity. These compounds are currently being evaluated in cellular and animal models of cancer and could be exploited for the diagnosis, staging, and potential treatment of solid tumors.
- © 2009 by Society of Nuclear Medicine