An astatine-211 labeled PSMA inhibitor for targeted alpha-particle radiotherapy of prostate carcinoma

Objectives Urea-based prostate-specific membrane antigen (PSMA) inhibitors labeled with ¹⁸F, radioiodine and radiometals are promising agents for imaging prostate cancer (PCa). Because of their low molecular weight and rapid normal tissue clearance, these molecules might be ideal for selectively delivering the 7.2-h half life α-particle emitter ²¹¹At to PCa cells.

Methods The target compound, 2-[3-[5-(4-[²¹¹At]astato-benzoylamino)-1-carboxy-pentyl]-ureido]-pentanedioic acid (ABCPUP) and its ¹³¹I-labeled analogue, CIBPUP were synthesized in two steps from a protected tin precursor. Their uptake was determined in a paired-label study with PSMA positive PC3 PIP and PSMA negative PC3 FLU cells.

Results After a 10 min reaction, the average radiochemical yields for the astatination of tin precursor was 78.3 ± 12.2% (n = 4), which was comparable to radioiodination yields (76.5 ± 7.4%; n = 2); deprotection was quantitative. The uptake (% input dose per 5 x 10⁵ cells) of both ABCPUP and CIBPUP in PIP cells increased with time (4.9 ± 0.3% and 19.3 ± 0.9% for ABCPUP and 5.0 ± 0.3% and 22.3 ± 1.1% for CIBPUP at 30 min and 4 h, respectively; p < 0.05 for ABCPUP versus CIBPUP). The uptake of both tracers was reduced to less than 4% of controls when co-incubated with 2-PMPA, an inhibitor of PSMA. For both tracers, the absolute uptake in FLU cells ranged from 0.01 – 0.04%.

Conclusions Substitution of ²¹¹At for iodine in this compound did not result in any alteration in specificity of its binding to PCa cells. ABCPUP warrants further evaluation as a targeted radiotherapeutic for the treatment of PCa.

Research Support NIH grants CA42324, CA92871