Recent progress on the production of 72As (2.49 MeV β+avg, t½=26.1 h) and 77As (0.225 MeV β−avg, t½=38.8 h) has facilitated their evaluation as a potential “theranostic pair” for PET imaging and radiotherapy. Previously reported 77As-labeled trithiol bioconjugates showed high in vivo stability, but cleared through gastrointestinal system due to their high lipophilicity. In this work, a more hydrophilic trithiol chelator with two carboxylic acid groups was synthesized and conjugated to the RM2 peptide - a gastrin-releasing peptide receptor (GRPR) antagonist for targeting of GRPR in prostate cancer. No carrier added (nca) 77As was produced via neutron irradiation of enriched 76GeO2 followed by decay of 77Ge to 77As. Arsenic-77 was separated as [77As]H2AsO4- , which was reduced and complexed with a monothiol transfer ligand prior to radiolabeling. The chelator was conjugated to the RM2 peptide via solid phase peptide synthesis through two different linkers, Ser-Ser and Glu-Ser. The RM2 trithiol bioconjugates were radiolabeled with nca 77As and compared in initial biodistribution studies. Radiolabeling of the RM2 conjugates with 77As resulted in over 85% radiochemical yield for 77As-Ser-Ser-RM2 and 90% for 77As-Glu-Ser-RM2. Both radiotracers demonstrated excellent in vitro stability (≥ 90% remaining intact through 24 h in PBS buffer). Both tracers were found to be more hydrophilic (log D7.4: -0.2 for 77As-Ser-Ser-RM2 and -1.3 for 77As-Glu-Ser-RM2) than our previous version of 77As-ester-RM2 (log D7.4: 0.7). Biodistributions of both radiotracers in healthy CF-1 male mice demonstrated blockable pancreatic uptake (%ID/g at 1 h in pancreas: 11.0 for 77As-Ser-Ser-RM2 and 7.8 for 77As-Glu-Ser-RM2 vs. 1.9 and 1.8 with blocking, respectively) indicating specific GRPR uptake. Both radiotracers demonstrated mainly hepatobiliary clearance. Compared to 77As-Ser-Ser-RM2, 77As-Glu-Ser-RM2 showed slightly higher renal clearance (%ID/organ at 24 h in urine: 24.8 for 77As-Glu-Ser-RM2 vs. 18.3 for 77As-Glu-Ser-RM2) due to the higher hydrophilicity of Glu than Ser. Further studies to increase the hydrophilicity of the tracer for faster renal clearance are underway.

Development and biodistribution studies of 77as-labeled trithiol RM2 bioconjugates for prostate cancer

ACS Spring 2022

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