IVC-11: A tracer for targeting of α-methylacyl-CoA racemase (AMACR)

Objectives AMACR is overexpressed in prostate and other tumors but not in adjacent normal tissues. The aim of this work was identification of the marker suitable for specific molecular imaging of AMACR expression in vivo.

Methods ¹³¹I-ω-iodovinyl substituted fatty and malonic acids were synthesized and tested as CoA-thioesters on their ability to inhibit the AMACR-catalyzed epimerization of (R)-THC-CoA. Cell uptake in LNCaP, PC3 und DU145 prostate tumor cells with different AMACR expression level was studied. Biodistribution study was carried out in TRAMP mouse model.

Results Eight n.c.a. ¹³¹I-labeled compounds were prepared from Bu₃Sn-precursors with > 95% rp and in 15–39% rcy. The iodination of the precursors, followed by hydrolysis and coupling with CoA-H, gave the respective CoA-thioesters (10–75% yield on 3 steps). Only IVC-11-CoA (K_i = 37±7 μM) and IVMC-11-CoA were found to be AMACR-inhibitors. In contrast to those of ¹³¹I-IVMC-11, cell uptake of ¹³¹I-IVC-11 in LNCaP (1.75±0.15%, 2 h; 16.80±1.28%, 24 h), PC3 (1.28±0.67%, 2 h; 10.15±1.47%, 24 h) and DU145 (0.34±0.09%, 2 h; 0.41±0.04%, 24 h) cells correlated with AMACR expression. In TRAMP mouse model ¹³¹I-IVC-11 accumulated good in the AMACR-positive liver (%ID/g: 27.93±4.53, 1 h; 14.72±9.16, 4 h), kidneys (%ID/g: 11.65±1.82, 1 h, 5.68±0.62, 4 h) and stomach (%ID/g: 4.89±1.82, 1 h; 8.38±0.25, 4 h). Radioactivity enrichment in prostate varied strongly (%ID/g: 1.0–16.8, 4 h) from mouse to mouse and corresponded to the observed expression level of AMACR.

Conclusions (E/Z)-11-iodoundecen-10-ylmalonic acid (IVC-11) is a promising candidate for imaging of AMACR expression in vivo.