Arsenic-72 (β⁺3.33 MeV, t_1/2=26 h) and ⁷⁷As (β^-0.683 MeV, t_1/2=38.8 h) are a suitable radioisotope matched pair for development of theranostic radiopharmaceuticals. Bombesin (BBN) peptide analogues generally target gastrin-releasing peptide (GRP) receptors expressed in the pancreas of normal mice and human cancers of the prostate. Previous biodistribution studies with ⁷⁷As-trithiol(a)-BBN(7-14)NH₂(Figure 1a) in normal mice showed high in vivo stability compared to free ⁷⁷As (arsenate). However, the high lipophilicity of ⁷⁷As-trithiol(a)-BBN(7-14)NH₂resulted in predominantly hepatobiliary excretion and no significant pancreatic uptake. Here we report the development of a new, more hydrophilic trithiol bifunctional chelate with a Log D_7.4value of -1.45 (for ⁷⁷As-trithiol(b) complex) and flexibility in the structure for conjugation to targeting biomolecules. This new trithiol chelate was conjugated to the RM2 peptide (a GRP receptor antagonist) through a two serine (Ser) spacer. IC₅₀studies of ^natAs-trithiol(b)-(Ser)₂-RM2 (Figure 1b) showed 8.2 nM binding affinity with GRP receptor-expressing PC3 prostate cancer cells. The trithiol(b)-(Ser)₂-RM2 conjugate was radiolabeled with no carrier added ⁷⁷As and conditions were optimized to maximize radiolabeling yield. Limited biodistribution studies in normal mice were performed with HPLC-purified ⁷⁷As-trithiol(b)-(Ser)₂-RM2. These results will be reported.

Tammy Rold

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