4-[2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2-(S)-[N-3-amino-(SCN-Bz-DOTA-111In)-neopenta-1-carbamyl)]-aminoethylsulfonylamino-β-alanine (IAC-SCN-Bz-DOTA-111In) is an integrin-targeted molecular imaging agent conjugated with 111In that was developed for single-photon emission computed tomography (SPECT) or planar gamma imaging of tumor vasculature and tumor angiogenesis (1). 111In is a gamma emitter with a physical half-life (t½) of 2.8 days.
Cellular survival, invasion, and migration control embryonic development, angiogenesis, tumor metastasis, and other physiological processes (2, 3). Among the molecules that regulate angiogenesis are integrins, which comprise a superfamily of cell adhesion proteins that form heterodimeric receptors for extracellular matrix (ECM) molecules (4, 5). These transmembrane glycoproteins consist of two noncovalently associated subunits, α and β (18 α- and 8 β-subunits in mammals), which are assembled into at least 24 α/β pairs. Several integrins, such as integrin αvβ3, have affinity for the arginine-glycine-aspartic acid (RGD) tripeptide motif, which is found in many ECM proteins. Expression of integrin αvβ3 receptors on endothelial cells is stimulated by angiogenic factors and environments. The integrin αvβ3 receptor is generally not found in normal tissue, but it is strongly expressed in vessels with increased angiogenesis, such as tumor vasculature. It is significantly upregulated in certain types of tumor cells and in almost all tumor vasculature. Molecular imaging probes carrying the RGD motif that binds to the integrin αvβ3 can be used to image tumor vasculature and evaluate angiogenic response to tumor therapy (6, 7).
Various RGD peptides in both linear and cyclic forms have been developed for in vivo binding to integrin αvβ3 (8). Non-peptide integrin αvβ3–targeted molecular probes have also been investigated (9-11). Duggan et al. (10) modified a potent fibrinogen receptor antagonist from the sulfonamide exo-site class to generate non-peptide compounds with high affinity for the integrin αvβ3 receptor. The centrally -constrained benzoylamino-3-propionic acid scaffold appeared to provide optimum spacing between the acidic and basic portions of these ligands for binding. Based on the potent αvβ3 inhibitor 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-β-alanine (IA) which has a 50% inhibitory concentration (IC50) of 0.04 μM and was used by Hood et al. (11) to covalently couple to a cationic nanoparticle for targeted gene therapy, Burnett et al. (9) designed and synthesized a series of aliphatic carbamate derivatives with enhanced binding affinity. The peptidomimetic 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-β-alanine hydrochloride (IAC) ligand was conjugated to a fluorescence label (FITC-IAC) as an integrin αvβ3 molecular probe for optical imaging of αvβ3-expressing tumors. To develop a radioligand for SPECT imaging, Jang et al. (1) successfully prepared IAC-SCN-Bz-DOTA-111In for studies in nude mice bearing the human M21 melanoma tumor.