Abstract
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Objectives Hsp90 (heat shock protein 90) is an ATP dependent molecular chaperone which has emerged as a potent target of many cancer therapies. PU-H71 is a potent ATP competitive inhibitor (EC50 = 30 nm) of Hsp90. Our goal was to synthesize chemically identical, radioiodinated [124I]-PU-H71 by replacing the native iodine on the molecule with radioactive iodine and to carry out biodistribution and PET imaging studies.
Methods [124I]-PU-H71 was synthesized by iododestannylation of N-boc protected trimethyltin precursor with [124I]-NaI in presence of chloramine-T, followed by deprotection with 11 N HCl and purified by RP HPLC. For in vivo studies mice with MDA-MB-468 xenografts were used. [124I]-PU-H71 in saline (0.9%, pH 7) was administered via tail vein and the mice were used for biodistribution studies or imaging with MicroPET.
Results The radioiodination was high yielding reaction but byproduct formation was observed during the deprotection step. The overall synthetic yield of [[124I]-PU-H71 was ~50%, with specific activity of about 280 mCi/μmol and radiochemical purity >98%. Biodistribution and imaging studies reveal accumulation and retention of tracer in the tumor (0.20 ± 0.05 %ID/g at 24 h) while clearance from non-target organs by 24 h. The tumor to blood and tumor to muscle ratios at 24 h pi were >50.
Conclusions PU-H71 a potent Hsp90 inhibitor was radioiodinated with 50% overall yield and >98% purity. Because of identical chemical identity of radiotracer with therapeutic agent PU-H71 (currently under clinical trials as anti-cancer drug in various cancers), the radiotracer can be used for following pharamacokinetics and pharmacodynamics of the drug. Accumulation of radiotracer in tumor indicates that the tracer may hold potential in identifying Hsp90 overexpressing targets.
Research Support This work was partly supported by NIH grant P50 CA86438