Design, Synthesis, and Initial Evaluation of High-Affinity Technetium Bombesin Analogues

Abstract

Potent antagonists of bombesin-like peptides have shown great potential for applications in cancer therapy. A 99mTc-labeled agent capable of identifying patients who could benefit from these emerging therapies would have a great impact on patient management. This study involves the synthesis and initial evaluation of technetium diaminedithiolate analogues derived from the potent bombesin analogue Pyr-Gln-Lys-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (Lys3-bombesin). We coupled two diaminedithiol (DADT) bifunctional chelating agents (BCAs 1 and 2) to the Lys3 residue at the N-terminal region that is not required for binding to the receptor. 99mTc labeling was performed by ligand exchange on addition of [99mTc]glucoheptonate to a solution of the adduct at room temperature. Two products were obtained from each adduct on analysis by HPLC. The major to minor product ratios of the 99mTc-labeled analogues were 3:1 for products from BCA 1 and 9:1 for the products from BCA 2. Macroscopic amounts of the 99Tc analogues were similarly prepared using [99Tc]glucoheptonate. In this case, the major to minor ratios were 2:1 for the products from both BCAs. For initial evaluation of the binding of the Tc-labeled peptides to bombesin receptors, the 99Tc analogues were used in vitro in competitive binding assays in rat brain cortex membranes against [125I-Tyr4]bombesin. Results of the in vitro assays showed that the inhibition constants (Ki) of the major and minor products were 3.5+/-0.7 and 3.9+/-1.5 nM, respectively, for the products from BCA 1; and 7.4+/-2.0 and 5.2+/-1.5 nM for the products derived from BCA 2, respectively. The high affinity exhibited by these technetium analogues is an indication of their potential for use in non-invasive in vivo biochemical characterization of cancers that possess receptors for bombesin.

Synthesis and Evaluation of Bombesin Derivatives on the Basis of Pan-Bombesin Peptides Labeled with Indium-111, Lutetium-177, and Yttrium-90 for Targeting Bombesin Receptor-Expressing Tumors

“…Therefore, most radiolabeled bombesin-like peptides are based on the sequence bombesin (7-14) (10, 28 -31, 33-35). For example, different conjugates were developed using bifunctional chelators for labeling with 99m Tc, like N 2 S 2 (29), N 3 S (31), N ␣ -histidinyl acetate (35), and diaminopropionic acid (36), using the carbonyl approach. Also, diethylenetriaminepentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-N,NЈ,NЉ,Nٞ-tetraacetic acid (DOTA) were coupled to this sequence for labeling with hard Lewis acid radiometals like 111 In, 67, 68 Ga, 90 Y, and the lanthanides.…”

Re-188 Enhances the Inhibitory Effect of Bevacizumab in Non-Small-Cell Lung Cancer

“…Bevacizumab, monoclonal antibody, was directly labeled with 188 ReO 4 − by ligand exchange using 188 Re-glucoheptonate according to a published method [25,26]. Briefly, 100-200 µL of 188 ReO 4 − fresh perrhenate eluate (185-370 MBq) in normal saline were added to a solution containing 10 mg of sodium α-D-glucoheptonate dihydrate (dissolved in acetic acid, pH value of 2.5-7, 0.1 M), and treated with SnCl 2 (range 200-1500 µg) as reductant at room temperature for 30 min.…”

Synthesis of bombesin-functionalized iron oxide nanoparticles and their specific uptake in prostate cancer cells

“…In fact, there have been various radiolabeled bombesin conjugates containing extensive modifications to the N-terminus, which still retain high affinity for the desired receptors (Baidoo et al 1998;La Bella et al 2002;Smith et al 2003; Van de Wiele et al 2001). Consequently, most labeled bombesin analogs are simply modifications of this bombesin-(7-14) sequence (Baidoo et al 1998;La Bella et al 2002;Smith et al 2003; Van de Wiele et al 2001; Van de Wiele et al 2000). In this case, modification of the bombesin-(7-14) peptide was carried out to include a second β-alanine extension in position six, replacing the non-essential D-Tyr (Fig.…”