Novel radioiodinated theranostic agent targeting PSMA for Prostate cancer

383 Introduction: Prostate Specific Membrane Antigen is highly overexpressed in both primary and metastatic prostate cancer (PC) and therefore is a prime target for development of novel radiopharmaceuticals (RPs). Iodine has several easily available isotopes that can be used for SPECT (I-123), PET (I-124) or therapy (I-131) with long half-life and therefore offers unique advantages. However, the currently available radioiodinated PSMA targeting RPs involve multiple steps for their production which reduces their yields and poses significant challenges for producing therapeutic doses. To overcome these limitations, we have developed a novel radioiodinated PSMA targeting RP[124/131I]-MSK-PSMA1, that can be produced in quantitative yields in a single step from easily available chemical precursor DKFZ-PSMA11 (DP11). In this study, we present synthesis, in vitro cell binding assays and in vivo PET imaging and biodistribution studies in a PSMA expressing xenograft model. Methods: [124/131I]-MSK-PSMA1 was synthesized by incubation of DP11 in saline with [124/131I]-NaI in presence of chloramine-T for 2 min followed by purification on C-18 cartridge. In vitro saturation binding assay was performed on LNCaP and PC3-PIP cells (106) by incubating (1 h) with increasing concentrations of [131I]-PSMA ranging from300-0.1nM. The cells were harvested and counted for radioactivity using gamma counter. The data obtained was analyzed by GraphPad Prism to determine Bmax and Kd of [131I]-PSMA for both the cell lines. In vivo PET imaging and biodistribution studies were performed on athymic nude mice bearing PC3-PIP xenografts. For PET imaging studies, [124I]-MSK-PSMA1 was administered i.v. via tail vein and mice are imaged at 1, 4, 24, 48, 96 and 168 h after injection. For biodistribution study [131I]-MSK-PSMA1 was administered i.v. and mice were euthanized 1, 2, 6 and 24 h post injection and organs are collected, weighed and measured for radioactivity. %ID/g of [131I]-PSMA for each organ is determined. Results: [124/131I]-MSK-PSMA1 was synthesized in >90% yields in specific activity >100 mCi/µmole. In vitro binding assays in LNCaP reveal specific binding with Bmax 492999 and Kd 13.87 nM which are comparable to 68GA labelled PSMA ligand in LNCaP cells. Bmax and Kd in PC3-PIP cells are 2600497 and 27.27 nM respectively. PET imaging studies shows specific uptake in tumor which can be clearly imaged and measured up to 168hours post injection with very minimal background. There is additional uptake in kidneys (which also expresses biological PSMA in mice) and bladder through which the unbound ligand is cleared rapidly than from tumor. Biodistribution studies reveal uptake in tumor to be 6.3, 20.2, 15.0, 9.7 %ID/g at 1, 4, 6 and 24 h respectively. Conclusions: We have successfully developed a novel radioiodinated PSMA targeting theragnostic radiopharmaceutical that can be synthesized easily in one step and purified without the need of HPLC purification. In vitro and in vivo studies in prostate cancer cell and tumor xenograft models indicate high specificity, favorable pharmacokinetics and rapid clearance from non-target tissue. Owing to ease of synthesis, we believe MSK-PSMA1 will find wide applicability. In vivo therapeutic efficacy studies are currently underway.