title: Targeting of CCK-2 receptor-expressing tumors using a radiolabeled divalent gastrin peptide.
abstract: Gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) are overexpressed in several tumor types and are, thus, a potential target for peptide receptor radionuclide therapy (PRRT) of cancer. To improve the in vivo performance of CCK-2R binding peptides, we have previously synthesized and screened a series of divalent gastrin peptides for improved biochemical and biologic characteristics. In this study, we explore in more detail the most promising of these compounds and compare its performance with a previously described monomeric peptide.
  
  
  METHODS
  From six (111)In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-conjugated divalent gastrin peptides based on the C-terminal sequence of minigastrin, the maleimide-linked compound DOTA-GSC(succinimidopropionyl-EAYGWNleDF-NH(2))-EAYGWNleDF-NH(2) (MGD5) was selected. The in vitro stability, receptor binding, and internalization of (111)In-MGD5 were studied and compared with those of monomer compound (111)In-APH070. In vivo biodistribution and imaging using a SPECT/CT camera were also performed.
  
  
  RESULTS
  More than 90% of the labeled divalent peptide remained intact after 20 h of incubation in plasma. The inhibitory concentration of 50% of the divalent peptide was 1.0 versus 5.6 nM for the monomer, and the dissociation constant was 0.7 versus 2.9 nM. The rate of internalization of the divalent peptide was twice that of the monomer. Tumor uptake of the divalent peptide in vivo was about 6 times that of the monomer. The rate of washout of the divalent peptide from the tumor was lower than that of the monomer.
  
  
  CONCLUSIONS
  Dimerization of the CCK-2R binding site results in an increase in binding affinity and an increase in tumor uptake both in vitro and in vivo. It is likely that these increases would result in improved tumor-targeting efficiency in patients with CCK-2R-positive tumors.
authors.affiliation: Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom. j.k.sosabowski@qmul.ac.uk
authors.forename: Jane K
authors.initials: JK
authors.lastname: Sosabowski
authors.forename: Torkjel
authors.initials: T
authors.lastname: Matzow
authors.forename: Julie M
authors.initials: JM
authors.lastname: Foster
authors.forename: Ciara
authors.initials: C
authors.lastname: Finucane
authors.forename: David
authors.initials: D
authors.lastname: Ellison
authors.forename: Susan A
authors.initials: SA
authors.lastname: Watson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mather
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005755:Gastrins / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007553:Isotope Labeling; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D005755:Gastrins; D006573:Heterocyclic Compounds, 1-Ring; D043887:Receptor, Cholecystokinin B; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid