Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Abstract

Purpose: 123 I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, 123 I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize 123 I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials. Materials and methods: 123 I-MAPi was prepared in a single step via 123 I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of 123 I-MAPi in a small cell lung cancer model. Results: 123 I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq mmol À1. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation. Conclusions: Here, we have developed an improved radiosynthesis of 123 I-MAPi, an Auger theranostic agent. This process was achieved using a single step, 123 I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. 123 I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

“…In this study, we reported the synthesis of a PARP1 specific, olaparib derived Auger emitting PARPi: [ 125 I]-PARPi-01. Our radiosynthesis yielded up to 2.5 times higher molar activity and significantly higher radiochemical yield than reported by Wilson et al [ 24 ]. Here, we demonstrate an efficient induction of highly damaging DNA double strand break (γH2AX foci) and significantly reduced tumorigenicity, upon treatment (72 h) with [ 125 I]PARPi-01, at molar concentrations of 0.01–0.04 µM.…”

“…No deiodination was observed upon long-term storage at −20 °C in ethanol ( Figure S2B ). During the course of this study, Wilson et al reported a similar facile approach for the synthesis of the structurally similar Auger emitting theranostic [ 123 I]-MAPi, but with a significantly lower yield (45 ± 2%) and low molar activity (11.8 ± 4.8 GBq/µmol) [ 24 ]. The target specificity of the synthesised [ 125 I]-PARPi-01 was evaluated in vitro (in MDA-MB-231 cells) by a blocking assay upon co-treatment of [ 125 I]-PARPi-01 (1 nM) with 100× higher molar concentration of olaparib (100 nM).…”

“…Therefore, at the molecular level the AE radiolabelled PARPis bind and block the PARP1 mediated DNA repair, along with causing further DNA damage contributing to a two-hit therapy approach. Currently, Auger emitter radionuclide 123/125 I have been radiolabelled in two FDA-approved PARPi backbones - olaparib: [ 123 I]-MAPi (structurally similar to our probe) [ 24 ] and Rucaparib: [ 123/125 I]-KX1 [ 46 ]. During the course of this study, preclinical therapeutic evaluation of 123 I-MAPi was reported in glioblastoma models, in which a significant survival advantage was shown upon delivering the [ 123 I]-MAPi via local intratumoral injection or delivery.…”

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

“…In this setup, survival increased from 48 days in the control group to 72 days in the treated group and the treatment was tolerated well by the animals [ 97 ]. Subsequently, an improved synthesis route for the 123 I-labeling was developed using a single step 123 I-iododestannylation reaction, yielding higher molar activity (A m ) of 11.8 GBq/µmol compared to previous work with A m = 3.9 GBq/µmol [ 98 ]. While intratumoral injection might be considered for glioblastoma treatment clinically, for other tumor entities, it is not an option.…”

Rapid detection of SARS-CoV-2 using a radiolabeled antibody

“…Based on our early work using an oncology-inspired strategy to radiolabel viruses [ 8 ], and our previous experience with radioiodinated agents for nuclear medicine applications [ [19] , [20] , [21] , [22] ], here we explored a novel, fast, and inexpensive method for the direct detection of SARS-CoV-2 virions in saliva samples. Unlike the other methods already in use [ 23 ], our technology directly targets S1 spike proteins on the surface of viable viruses using a radioactive detection output.…”