Studies on the Synthesis and Biological Properties of Non-Carrier-Added [¹²⁵I and ¹³¹I]-Labeled Arylalkylidenebisphosphonates:  Potent Bone-Seekers for Diagnosis and Therapy of Malignant Osseous Lesions

Abstract

Arylalkylidenebisphosphonates labeled with nca [(125)I or (131)I] have been synthesized and their biological function investigated. The label was attached to the aromatic group in high yield and under mild conditions by means of iododesilylation. The bone affinities of the radioactive compounds were investigated in normal Balb/C mice. The compound 1-hydroxy(m-iodo[(125,131)I]-phenylethylidene)-1,1-bisphosphonate was found to possess superior bone affinity compared to others, and its in vivo deiodination was insignificant. The uptake in femur 24h after injection was 850 +/- 265% and 986 +/- 118% of injected dose per gram tissue times gram body weight in mice and rats, respectively. The therapeutic potential of the compound was investigated in two tumor models in athymic (nude) rats, one model for mixed lytic/sclerotic metastatic bone-lesions originating from breast cancer and the other model simulating osseous osteosarcoma. The effects in these models compare favorably to those observed for established treatment modalities. The experiments demonstrate that radioiodinated bisphosphonates may have a potential for diagnosis and therapy of malignant osseous lesions.

Synthetic Procedures Leading towards Aminobisphosphonates

“…Because this compound was previously prepared by acid hydrolysis of N-benzhydrylaminomethylenebisphosphonic acid [83,100], it may be that it is formed upon hydrolysis of N-aryl derivatives. The three-component reaction was applied to synthesize a large series of physiologically active compounds, in some cases of very complex chemical structures, including bone antiresorptive drug candidates [75][76][77][78][79][80][81][82]; bone imaging [83,84], antiprotozoal [85][86][87][88], antibacterial [72,[89][90][91][92], anti-HIV [93] and anti-inflammatory [94] agents; herbicides [95][96][97]; and complex ones for various metals [10,98].…”

1-Amino-1,1-bisphosphonates. Fundamental syntheses and new developments

“…11,84,89 Of recent studies, should be mentioned synthesis of non-carrier-added (nca) 131 Ilabeled bisphosphonic acid 57 by the reaction of the amine 55 with triethyl ortoformate and diethyl phosphite followed by iododesilylation (Scheme 21). 92 Another recent example is threecomponent reaction between aminoadamantanes 58, triethyl ortoformate and diethyl phosphite which was used to obtain bisphosphonates 59. This conversion was carried out under microwave irradiation (400 W, 150 o C).…”

Enhanced Affinity Bifunctional Bisphosphonates for Targeted Delivery of Therapeutic Agents to Bone

“…Moreover, in addition to being prescribed as drugs, BPs are also being studied for drug targeting, and drug delivery to bone, 25–30 including the administration of radiopharmaceuticals and imaging agents to bone for diagnostic applications. 31–35 For the purpose of drug targeting to bone, various strategies of BP-drug conjugation have been investigated by us and others. 29,35–38 Ideally, for targeted drug delivery to bone, BP-drug conjugates should have a stable linkage between the BP and drug molecule that can survive during systemic circulation of the conjugate following parenteral administration, and at the same time be labile at the bone surface to release the drug locally.…”

“…31–35 For the purpose of drug targeting to bone, various strategies of BP-drug conjugation have been investigated by us and others. 29,35–38 Ideally, for targeted drug delivery to bone, BP-drug conjugates should have a stable linkage between the BP and drug molecule that can survive during systemic circulation of the conjugate following parenteral administration, and at the same time be labile at the bone surface to release the drug locally. Most of the strategies mentioned above employ agents that are conjugated to BPs through stable, non-cleavable linkages resulting in the administration of the complete conjugate to the treatment site.…”

“…Most of the strategies mentioned above employ agents that are conjugated to BPs through stable, non-cleavable linkages resulting in the administration of the complete conjugate to the treatment site. 25,29,31–33,35 Current approaches that employ cleavable linkages are either too labile to ensure delivery of the drug to the desired site, 26,27 or show limited release providing inadequate availability of drug for action. 26 A strategy that involves labile conjugation to one of the phosphonate groups of BP could compromise the affinity of the corresponding BP-drug conjugate toward bone, because it is through the phosphonate groups that BPs bind to the mineral matrix.…”