title: Radiolabeled divalent peptidomimetic vitronectin receptor antagonists as potential tumor radiotherapeutic and imaging agents.
abstract: The integrin receptor alphavbeta3 is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. A radiolabeled alphavbeta3 antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138) was previously shown to exhibit high affinity for integrin alphavbeta3 and high selectivity versus other integrin receptors. 111In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and produced excellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and their evaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of the spacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteic acid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays, and biodistribution studies using the 111In-labeled derivatives were carried out in the c-neu Oncomouse model. All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight 111In derivatives exhibited blood clearance that was faster than 111In-TA138 at 24 h postinjection (PI). All divalent agents exhibited tumor uptake and retention at 24 h PI that was higher than 111In-TA138. Tumor/organ ratios were improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver, with the agents having intermediate-length spacers (29-43 A) showing the largest improvement. As an example, 111In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney, 7.29; liver, 8.51. A comparison of therapeutic indices for 90Y-TA138 and 177Lu-15 indicate an improved therapeutic index for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalent effect are discussed.
authors.affiliation: Discovery Research, Bristol-Myers Squibb Medical Imaging, North, Billerica, Massachusetts 01862, USA. tdharris911@comcast.net
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Harris
authors.forename: Edward
authors.initials: E
authors.lastname: Cheesman
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Harris
authors.forename: Richard
authors.initials: R
authors.lastname: Sachleben
authors.forename: D Scott
authors.initials: DS
authors.lastname: Edwards
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Judit
authors.initials: J
authors.lastname: Bartis
authors.forename: Charles
authors.initials: C
authors.lastname: Ellars
authors.forename: Dave
authors.initials: D
authors.lastname: Onthank
authors.forename: Padmaja
authors.initials: P
authors.lastname: Yalamanchili
authors.forename: Stuart
authors.initials: S
authors.lastname: Heminway
authors.forename: Paula
authors.initials: P
authors.lastname: Silva
authors.forename: Simon
authors.initials: S
authors.lastname: Robinson
authors.forename: Joel
authors.initials: J
authors.lastname: Lazewatsky
authors.forename: Milind
authors.initials: M
authors.lastname: Rajopadhye
authors.forename: John
authors.initials: J
authors.lastname: Barrett
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy; D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy; D003952:Diagnostic Imaging; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007205:Indium Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008187:Lutetium / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D010455:Peptides; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D013449:Sulfonamides; C485703:TA 138; D008187:Lutetium