The automated synthesis and initial in vivo evaluation of 212Pb-RM2 as a potential targeted alpha therapeutic agent for treatment of prostate cancer are described. 212Pb-RM2 is a radiolabeled peptide conjugate that targets the bombesin receptor (BB2r), which is frequently over-expressed in human prostate cancer cells. Alpha particles emitted from 212Bi (t1/2 = 60.6 minutes), the daughter product of 212Pb (t1/2 = 10.6 hours) decay, have significant cytotoxic potential due to their high liner energy transfer properties. Using 212Pb as an in vivo generator of 212Bi significantly compensates for the shorter half-life of 212Bi, and allows sufficient time for the preparation, administration, and in vivo accumulation of the radiopharmaceutical at its target site. Prior to radiolabeling, 212PbCl2, eluted from a 224Ra/212Pb generator, was purified using a Pb-selective ion exchange resin (Pb-resin). RM2 (RM2= DOTA- 4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) radiolabeling was performed by incubating purified 212Pb2+ solution in 0.5M NaOAc buffer (pH 6) with the RM2 peptide conjugate at 85 °C for 20 min, using an automated cassette-based radiosynthesis device. Quality control of the final product was performed using radio-HPLC. In vivo stability and biodistribution of 212Pb-RM2 was evaluated in CF1 normal mice at 15min, 1hr, 4hrs, 24hrs, and 48hrs post injection. 212Pb-RM2 was synthesized in ≥90% radiochemical purity and ≥85% yield. In vivo stability of 212Pb-RM2 was confirmed by minimal drug uptake in the critical non-target organs of kidneys, liver, and bone with 0.79 ± 0.29 %ID/g, 0.06 ± 0.02 %ID/g, and 0.07 ± 0.08 %ID/g, respectively at 24 hours post injection. These organs have been previously shown to preferentially accumulate free Pb over time. The biodistribution and in vivo stability of 212Pb-RM2 supports further evaluation of this radiopharmaceutical as a therapeutic option for prostate cancer. The described automated synthesis method is applicable for translation into clinical settings.

Synthesis of 212Pb-RM2: A potential radiotherapeutic agent for prostate cancer

255th National Meeting (2018)

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