Synthesis and preclinical evaluation of peptide receptor-targeted diagnostic and therapeutic radiopharmaceuticals for prostate cancer

Abstract

The overexpression of certain peptide receptors on cancers cells can be exploited for the development of radiopharmaceuticals that are selectively delivered to cancer cells for diagnostic imaging or therapeutic purposes. Parts of this dissertation explore the development and preclinical evaluation of a radiolabeled antagonist peptide conjugate (RM2 = DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) that targets the bombesin receptor (BB2r) overexpressed in human prostate cancer. Two radionuclides, [203]Pb and [212]Pb, were selected due to their uniqueness as a chemically identical theranostic matched pair. Lead--203 (t1/2 = 51.9 hours) decays by electron capture to stable [203]Tl, with the emission of [278] keV gamma rays (81% intensity) suitable for single-photon emission computed tomography (SPECT) imaging. On the other hand, [212]Pb (t1/2 = 10.6 hours) decays by beta emission into [212]Bi (t1/2 = 60.6 minutes), which subsequently decays into stable [208]Pb through a branched decay chain consisting of one alpha particle and one beta particle emission in each decay pathway. Hence, [212]Pb is of interest as an in vivo generator of [212]Bi for targeted alpha therapy. The fundamental chemistry and radiochemistry involved in the synthesis, purification and characterization of both [203Pb]Pb-RM2 and [212Pb]Pb-RM2 is described. Additionally, in vivo preclinical evaluation of the radiolabeled peptide conjugates was performed in male mouse models inoculated with PC3 human prostate cancer cells. The last portion of the work described in this dissertation focuses on 105Rh as a potential therapeutic radionuclide. Rhodium-105 (t1/2 = 35.4 hours) is a moderate energy beta-emitting radionuclide [ [beta] avg = 152 keV], with low energy gamma emissions [319 keV (19%) and 306 keV (5%)]. The production of 105Rh from recycled 104Ru metal target via the 104Ru (p, n) 105Ru -> 105Rh reaction was reported. In addition, a microwave-assisted procedure for the synthesis of Rh(III) complexes without the addition of refluxing ethanol or SnCl2 as reducing agents is described.