^99mTc-Labeling and in Vivo Studies of a Bombesin Analogue with a Novel Water-Soluble Dithiadiphosphine-Based Bifunctional Chelating Agent

Abstract

Recent progress in the synthesis of water-soluble phosphine ligand systems and their corresponding 99mTc complexes prompted the development of a new bifunctional chelating agent (BFCA) based on a tetradentate dithiadiphosphine framework (P2S2-COOH). The detailed synthesis of this new BFCA is described here. The corresponding 99mTc complex, 99mTc-P2S2-COOH, can be formed in >95% yield. To demonstrate the potential of this chelate to efficiently label peptides, 99mTc-P2S2-COOH was coupled to the N-terminal region of the truncated nine-amino acid bombesin analogue, 5-Ava-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 [BBN(7-14)], to form 99mTc-P2S2-BBN(7-14). Conjugation to the peptide was performed in borate buffer (pH 8.5) by applying the prelabeling approach in yields of >60%. In competitive binding assays, using Swiss 3T3 mouse fibroblast cells against [125I-Tyr4]bombesin, Re-P2S2-BBN(7-14) exhibited an IC50 value of 0.8 +/- 0.4 nM. The pharmacokinetic studies of 99mTc-P2S2-BBN(7-14) and its ability to target tissue expressing gastrin-releasing peptide (GRP) receptors were performed in normal mice. The 99mTc-P2S2-BBN(7-14) exhibited fast and efficient clearance from the blood pool (0.6 +/- 0.1% ID, 4 h postinjection) and excretion through the renal and hepatobiliary pathways (56.4 +/- 8.2 and 28.1 +/- 7.9% ID, 4 h postinjection, respectively). Significant uptake in the pancreas was observed (pancreatic acini cells express bombesin/GRP receptors), producing pancreas:blood and pancreas:muscle ratios of ca. 22 and 80, respectively, at 4 h postinjection.

Targeting prostate cancer with radiolabelled bombesins

“…Thus, coupling of air-stable hydrophilic phosphine containing P 2 S 2 -chelators to BB (7)(8)(9)(10)(11)(12)(13)(14) yielded radiotracers of high receptor affinity and good GRP-R-targeting in mice [35,36] . Alternatively, acyclic tetraamines have been coupled to both BB and BB (7)(8)(9)(10)(11)(12)(13)(14) to afford high specific activity radiotracers which localised in high percentage in human PC-3 xenografts in nude mice (up to 11%ID/g at 1 h pi) [37] .…”

Imaging Primary Prostate Cancer and Bone Metastasis

“…Gamma-emitting (y) '^""Tc labeled bombesin analogs have been synthesized and evaluated in vivo in normal mice (22,23) and PC-3 tumor-bearing mice (24,25), and have undergone feasibility testing in human patients (21). Although y emitters currently are more readily available relative to positron (P"^) emitting radionuclides, the sensitivity of PET is at least 1-2 orders of magnitude better than that of single photon imaging systems (26).…”

Mono‐, bi‐, or tridentate ligands? The labeling of peptides with 99mTc‐carbonyls

“…[5][6][7][8] More than one decade ago, the idea arose to combine 99m Tc with targeting agents (magic bullets). Targeting radiopharmaceuticals labeled with 18 F, 11 C, and various iodine isotopes have been in use for a much longer time, but the tendency is clearly to replace these short-lived radionuclides with 99m Tc for economic reasons. The radionuclides 18 F and 11 C are positron emitters and used in positron emission tomography (PET), whereas 99m Tc is a ␥-emitter for single photon emission tomography (SPECT).…”

“…Still, for reasons not outlined in detail here, SPECT is considered favored over PET. The main advantage of 99m Tc over 18 F and 11 C is its instant availability in hospitals by convenient 99 Mo/ 99m Tc generator systems, which reduce its price substantially. Furthermore, 99m Tc has a favorable decay characteristic that allows good imaging without a high dose burden to the patient.…”

“…Antibodies might represent an exception, and one peptide has now been Food and Drug Administration (FDA) approved. 6 -8 The reason for the failure is related to the authenticity of Tc, which belongs to the transition elements and requires, for stabilization, a coordination sphere rather than just one single bond (as in the case of 18 F or 123 I). Obviously, this renders the label rather bulky and significantly affects the biological behavior.…”