Synthesis and characterization of αvβ₃-targeting peptidomimetic chelate conjugates for PET and SPECT imaging

Abstract

There is growing interest in small peptidomimetic α(v)β(3) integrin antagonists that are readily synthesized and characterized and can be easily handled using physiological conditions. Peptidomimetic 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonyl-amino-β-alanine (IAC) was successfully conjugated to 1-(1-carboxy-3-carbo-t-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODA-GA(tBu)(3)) and 1-(1-carboxy-3-carbotertbutoxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA-GA(tBu)(4)) and radiolabeled with (111)In, (67)Ga and (203)Pb. Results of a radioimmunoassay demonstrated binding to purified α(v)β(3) integrin when 1-4equiv of integrin were added to the reaction. Based on this promising result, investigations are moving forward to evaluate the NODA-GA-IAC and DOTA-GA-IAC conjugates for targeting tumor associated angiogenesis and α(v)β(3) integrin positive tumors to define their PET and SPECT imaging qualities as well as their potential for delivery of therapeutic radionuclides.

Published by Elsevier Ltd.

Figures

Figure 1

Structures of NOTA derivatives. 7-(5-Maleimido-1-ethoxycarbonylphenyl)-1,4,7-triazacyclononane-1,4-diylacetic acid (1), 2-(4-Aminobutyl)-1,4,7-triazacyclononane-1,4,7-triyltriacetic acid (2), nNOTA (3), p-SCN-Bn-NOTA (4), NETA (5), and NODA-GA(tBu)3 (6).

Figure 2

Radio-HPLC profiles of 111In-1, A; 67Ga-1, B; and 203Pb-4, C and

Figure 3

HPLC profiles of Ga(III)-1 (top) and 67Ga-1 (bottom)

Figure 4

HPLC profiles of Pb(II)-4 (top) and 203Pb-4 (bottom).

Scheme 1

Synthesis of compound 1.

Scheme 2

Synthesis of compound 4.