title: Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors.
abstract: BACKGROUND
  The αvβ3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of αvβ3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with αvβ3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with (99m)Tc. In an effort to begin to address this limitation, we evaluated the tumor uptake of (99m)Tc-NC100692, a cyclic RGD peptide that binds to αvβ3 with ~1-nM affinity, in an αvβ3-positive tumor model as well as its in vivo specificity.
  
  
  METHODS
  MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for αvβ3, to block and displace (99m)Tc-NC100692 in an orthotopic U87 glioma tumor. The specificity of (99m)Tc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of (99m)Tc-NC100692 with that of the non-specific structural analogue (99m)Tc-AH-111744 and by blocking uptake of (99m)Tc-NC100692 with excess unlabeled NC100692.
  
  
  RESULTS
  MicroSPECT imaging studies demonstrated that uptake of (99m)Tc-NC100692 in the intracranial tumor model was both blocked and displaced by the αvβ3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of (99m)Tc-NC100692 at 1h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for (99m)Tc-AH-111744 (p < 0.001). Blocking (99m)Tc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 ± 0.3% ID/g (p = 0.01).
  
  
  CONCLUSIONS
  These results confirm that (99m)Tc-NC100692 does, in fact, target the αvβ3 integrin and may, therefore, be useful in identifying patients prior to anti-αvβ3 therapy as well as monitoring the response of these patients to therapy.
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA. jason.dearling@childrens.harvard.edu
authors.forename: Jason L J
authors.initials: JL
authors.lastname: Dearling
authors.forename: Jessica W
authors.initials: JW
authors.lastname: Barnes
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.forename: Robert E
authors.initials: RE
authors.lastname: Zimmerman
authors.forename: Frederic
authors.initials: F
authors.lastname: Fahey
authors.forename: S Ted
authors.initials: ST
authors.lastname: Treves
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Morrison
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Alan B
authors.initials: AB
authors.lastname: Packard
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging; D015609:Organotechnetium Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000378:metabolism* / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D039302:Integrin alphaVbeta3; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; C514230:technetium 99m NC 100692
keywords: Angiogenesis; Brain tumor; Cilengitide; MicroSPECT; NC100692; RGD peptides; α(v)β(3)