Pentavalent rhenium-188 dimercaptosuccinic acid for targeted radiotherapy: synthesis and preliminary animal and human studies

Abstract.

Pentavalent rhenium-188 dimercaptosuccinic acid [¹⁸⁸Re(V)DMSA] is a β-emitting analogue of ^99mTc(V)DMSA, a tracer that is taken up in a variety of tumours and bone metastases. The aim of this study was to develop the kit-based synthesis of the agent on a therapeutic scale, to assess its stability in vivo, and to obtain preliminary biodistribution and dosimetry estimates, prior to evaluation of its potential as a targeted radiotherapy agent. The organ distribution of ¹⁸⁸Re in mice was determined 2 h after injection of 3 MBq ¹⁸⁸Re(V)DMSA prepared from eluate from a ¹⁸⁸W/¹⁸⁸Re generator. Three patients with cancer of the prostate and three with cancer of the bronchus, all with bone metastases confirmed with a standard ^99mTc-hydroxymethylene diphosphonate (^99mTc-HDP) scan, were given 370 MBq ¹⁸⁸Re(V)DMSA and imaged at 3 h and 24 h using the 155-keV γ-photon (15%). Blood and urine samples were collected to determine clearance and to analyse the speciation of ¹⁸⁸Re. Organ residence times were estimated from the scans, and used to estimate radiation doses using MIRDOSE 3. In mice, ¹⁸⁸Re(V)DMSA was selective for bone and kidney. In patients, it showed selectivity for bone metastases (particularly those from prostate carcinoma) and kidney, but uptake in normal bone was not significantly greater than in surrounding soft tissues. Of the normal tissues the kidneys received the highest radiation dose (0.5–1.3 mGy/MBq). The images were strongly reminiscent of ^99mTc(V)DMSA scans in similar patients. High-performance liquid chromatography analysis of blood and urine showed no evidence of ¹⁸⁸Re in any chemical form other than ¹⁸⁸Re(V)DMSA up to 24 h. In conclusion, ¹⁸⁸Re(V)DMSA and its ¹⁸⁶Re analogue warrant further clinical assessment as generator/kit-derived agents for treatment of painful bone metastases. These agents should also be assessed in medullary thyroid carcinoma and other soft tissue tumours which have been shown to accumulate ^99mTc(V)DMSA.