Syntheses and evaluation of ⁶⁸Ga‐ and ¹⁵³Sm‐labeled DOTA‐conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases

Abstract

This article reports the syntheses and evaluation of Ga- and Sm-complexes of a new DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-conjugated geminal bisphosphonate, DOTA-Bn-SCN-BP, for their potential uses in the early detection of skeletal metastases by imaging and palliation of pain arising from skeletal metastases, respectively. The conjugate was synthesized in high purity following an easily adaptable three-step reaction scheme. Gallium-68- and Sm-complexes were prepared in high yield (>98%) and showed excellent in vitro stability in phosphate-buffered saline (PBS) and human serum. Both the complexes showed high affinity for hydroxyapatite particles in in vitro binding study. In biodistribution studies carried out in normal Wistar rats, both the complexes exhibited rapid skeletal accumulation with almost no retention in any other major organ. The newly synthesized molecule DOTA-Bn-SCN-BP would therefore be a promising targeting ligand for the development of radiopharmaceuticals for both imaging skeletal metastases and palliation of pain arising out of it in patients with cancer when radiolabeled with Ga and Sm, respectively. A systematic comparative evaluation, however, showed that there was no significant improvement of skeletal accumulation of the Sm-DOTA-Bn-SCN-BP complex over Sm-DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid) as the later itself demonstrated optimal properties required for an agent for bone pain palliation.

68Ga-P15-041, A Novel Bone Imaging Agent for Diagnosis of Bone Metastases

“…The kinetic data and SUVmax values observed in these patients were very consistent with those previously reported by Doot et al (16), which confirming the reproducibility of this tracer on detecting metastasis in cancer patients at different nuclear medicine departments. There are several other 68 Ga labeled bisphosphonates which have appeared in the literature (40)(41)(42)(43)(44)(45). No direct comparison of these tracers in cancer patients has been reported.…”

Synthetic Approaches to the Bifunctional Chelators for Radio­nuclides Based On Pyridine-Containing Azacrown Compounds

“…39 Three other approaches can be exploited, which do not affect on the coordination ability of macrocyclic moiety. In the presented approaches in Figure 1, the functional group can be attached to (i) one of the pyridine carbon, [40][41][42] (ii) one of the carbons of the ethylene group of the macrocyclic chelator backbone, [43][44][45][46][47] and (iii) one of the -positions to the carboxylic groups. 32,40,[48][49][50][51] In our research, the 4-position of the pyridine ring was chosen for modification due to big synthetic facilities in obtaining the acyclic pyridine precursors.…”

“…The choice of BFC is therefore governed by the thermodynamic and kinetic stability of the radiometal complexes. 6,[11][12][13][14] Fast room temperature radiolabeling becomes an important property when working with BFCconjugates of heat sensitive molecules such as antibodies and their derivatives, or when working with short half-life isotopes such as 212/213 Bi, 68 Ga, 44 Sc, and 62 Cu. [15][16][17][18][19][20]…”