A ^99mTc(I)-Postlabeled High Affinity Bombesin Analogue as a Potential Tumor Imaging Agent

Abstract

The overexpression of neuropeptide receptors observed in many cancers provides an attractive target for tumor imaging and therapy. Bombesin is a peptide exhibiting a high affinity for the gastrin releasing peptide (GRP) receptor, which is overexpressed by a variety of tumors such as breast or prostate cancer. In the present study, we have evaluated if the bombesin analogue [N(alpha)-histidinyl acetate]bombesin(7-14), radiolabeled with the novel [99mTc(OH(2))(3)(CO)(3)]+, has the potential to be used as a diagnostic radiopharmaceutical. Receptor saturation studies, carried out on the GRP receptor-expressing PC-3 human prostate cancer cell line, revealed for [99mTc(CO)(3)-N(alpha)-histidinyl acetate]bombesin(7-14) K(d) values in the subnanomolar range. Competitive binding assays, using the cold rhenium(I)-labeled analogue as a surrogate for the 99mTc-conjugate, also showed high affinity binding. Incubation of the radioconjugate with PC-3 cells resulted in a rapid temperature- and time-dependent specific internalization. At 37 degrees C more than 70% was internalized within the first 15 min and remained constant up to 2 h. Despite the weak proteolytic stability of [99mTc(CO)(3)-N(alpha)-histidinyl acetate]bombesin(7-14) in vitro, biodistribution studies, performed in PC-3 tumor-bearing mice, showed low uptake in the tumor (0.89 +/- 0.27% ID/g 30 min pi) but high uptake into the pancreas (7.11 +/- 3.93% ID/g 30 min pi), a GRP receptor-positive organ. Blockade experiment (coinjection of 300 microg bombesin/mouse with the radioligand) showed specificity of the uptake. Despite the low tumor uptake, tumor-to-blood ratios of 2.0 and 2.7 and tumor-to-muscle ratios of 8.9 and 8.0 were obtained at 30 min and 1.5 h postinjection, respectively. The promising results merit the future in vivo investigation of 99mTc/188Re-tricarbonyl-labeled bombesin analogues.

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

“…The residence times of both peptides in the tumor are not very long; this may originate from a somewhat low metabolic stability in the respective cells and may parallel the relatively low serum stability. Relatively fast tumor washout was also found for other radiometal-labeled, bombesin-based radiopeptides, for instance, 99m Tc-labeled bombesin(7-14) derivatives (34,35). The identification of the "weakest" peptide bond at ␤-Ala 11 -His 12 will help to improve the stability in future developments.…”

“…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.…”

Targeting prostate cancer with radiolabelled bombesins

“…A versatile route for labelling bombesin via the [ 99m Tc I -fac-(CO) 3 (H 2 O) 2 ] + -synthon [40] involved coupling of N α -histidinyl-acetic or 2-picolylamine-N,N-diacetic acid to BB (7)(8)(9)(10)(11)(12)(13)(14) [41,42] . But the resulting radiopeptides failed to accumulate effectively in PC-3 xenografts in nude mice (<0.6%ID/g at 1.5 h pi).…”

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.…”