RT Journal Article
SR Electronic
T1 Targeting of CCK-2 Receptor–Expressing Tumors Using a Radiolabeled Divalent Gastrin Peptide
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 2082
OP 2089
DO 10.2967/jnumed.109.064808
VO 50
IS 12
A1 Jane K. Sosabowski
A1 Torkjel Matzow
A1 Julie M. Foster
A1 Ciara Finucane
A1 David Ellison
A1 Susan A. Watson
A1 Stephen J. Mather
YR 2009
UL http://jnm.snmjournals.org/content/50/12/2082.abstract
AB 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 111In-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-NH2)-EAYGWNleDF-NH2 (MGD5) was selected. The in vitro stability, receptor binding, and internalization of 111In-MGD5 were studied and compared with those of monomer compound 111In-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. Conclusion: 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.