title: Imatinib analogs as potential agents for PET imaging of Bcr-Abl and c-KIT expression at a kinase level.
abstract: We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c-KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c-KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c-KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c-KIT, similarly to STI-571. [(18)F]-labeled STI-571 was prepared with high specific activity (75 GBq/μmol) by nucleophilic displacement and an average radiochemical yield of 12%. [(131)I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [(18)F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c-KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [(18)F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Maxwell
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Duoli
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Basvoju A
authors.initials: BA
authors.lastname: Bhanu Prasad
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Pal
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shimei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Julius
authors.initials: J
authors.lastname: Balatoni
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Pradip
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Seok T
authors.initials: ST
authors.lastname: Lim
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Volgin
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Shavrin
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: wbornmann@mdanderson.org.
authors.forename: William G
authors.initials: WG
authors.lastname: Bornmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001549:Benzamides / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use*; D049268:Positron-Emission Tomography / Q000379:methods*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl
keywords: Analog; Bcr-Abl; Imatinib; KIT; PET; Radiolabel; STI-571; c-KIT