Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151825 (bone pain)
 3,118 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-HEDP) has been used for the palliation of metastatic bone pain. Delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP in vivo. In this study, on the basis of the concept of bifunctional radiopharmaceuticals, we designed a stable 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate]oxorhenium(V) (186Re-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2-tritylmercaptoacetylamino)acetylamino]acetylamino]acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyl]glycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, 186Re-labeling was performed by reacting 186ReO4- with SnCl2 in citrate buffer. After purification by HPLC, 186Re-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of 186Re-MAG3-HBP and 186Re-HEDP, these (186)Re complexes were incubated in phosphate buffer. No measurable decomposition of 186Re-MAG3-HBP occurred over a 24-h period, while only approximately 30% of 186Re-HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of 186Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of 186Re-MAG3-HBP was faster than that of 186Re-HEDP. In addition, the gastric accumulation of 186Re-MAG3-HBP radioactivity was lower than that of 186Re-HEDP. In conclusion, 186Re-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.
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PMID:Development of a rhenium-186-labeled MAG3-conjugated bisphosphonate for the palliation of metastatic bone pain based on the concept of bifunctional radiopharmaceuticals. 1602 15

Rhemium-186-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP) has been used for the palliation of metastatic bone pain. However, delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP. We designed, synthesized and evaluated a stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl] carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re-MAG3-HBP). The stability of (186)Re-MAG3-HBP and (186)Re-HEDP in phosphate buffer were compared. No measurable decomposition of (186)Re-MAG3-HBP occurred, while only approximately 30% of (186)Re-HEDP remained intact 24 hours post-incubation. In biodistribution experiments, the radioactivity level of (186)Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of (186)Re-MAG3-HBP was faster than that of (186)Re-HEDP. In addition, the gastric accumulation of (186)Re-MAG3-HBP radioactivity was lower. To evaluate the therapeutic effects of (186)Re-MAG3-HBP, an animal model of bone metastasis was prepared. In the rats treated with (186)Re-HEDP, tumor growth was comparable to that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Bone pain was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective. These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent of metastatic bone pain. Moreover, based on the similar concept, we designed, synthesized, and evaluated a (99m)Tc-6-hydrazinopyridine-3-carboxylic acid-conjugated bisphosphonate ((99m)Tc-HYNIC-HBP) as a bone scintigraphic agent. (99m)Tc-HYNIC-HBP gave higher levels of radioactivity in bone than (99m)Tc-HMDP. There was no significant difference in clearance from blood between (99m)Tc-HYNIC-HBP and (99m)Tc-HMDP. Consequently, (99m)Tc-HYNIC-HBP showed a higher bone-to-blood ratio than (99m)Tc-HMDP. The findings indicate that (99m)Tc-HYNIC-HBP holds great potential for bone scintigraphy.
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PMID:[Development of radiopharmaceuticals for diagnosis and therapy of metastatic bone cancer]. 2303