Tc-99m-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer

293 Objectives PSMA is an attractive target for imaging and therapy of prostate cancer. Previously, we demonstrated successful 99mTc-based SPECT imaging of prostate cancer using urea-based PSMA inhibitors in mice. In those inhibitors ([99mTc]L1-6) a linker moiety was introduced between the amino functionalized PSMA urea and the technetium chelators utilizing a {99mTc(CO)3}+ moiety. Here we synthesized 14 new inhibitors ([99mTc]L7-20) to investigate the effect of different metal chelators on tumor uptake and pharmacokinetics in SCID mice bearing PC-3 PIP (PSMA+) and PC-3 flu (PSMA-) xenografts. This new series of inhibitors includes additional ligands for radiolabeling with {99mTc(CO)3}+ (L7-9), a hydrazino nicotinic acid (Hynic) chelator (L10) and traditional NxSy-based chelators for 99mTc-oxo labeling (L11-20). Methods Multi-step syntheses were employed in preparing L7-20 and selected rhenium analogs (ReL). Labeling with 99mTc was achieved either by using the Isolink kit (L7-9) or by standard SnCl2 reduction (L10-20). PSMA inhibitory capacities (L7-20, selected ReL) were evaluated by a competitive PSMA binding assay. In vivo characterization was performed by SPECT-CT (L7-20) and biodistribution studies ([99mTc]L8, [99mTc]L11, [99mTc]L18). Results Imaging demonstrated PSMA selective tumor uptake for all 99mTc-labeled compounds. The highest PSMA+ PC-3 PIP tumor uptake was achieved for [99mTc]L11 (42.5 ± 4 % ID/g) at 1 h, [99mTc]L8 (28.3 ± 4% ID/g) at 0.5 h and for [99mTc]L18 (28 ± 6 % ID/g) at 5 h. All compounds exhibited rapid blood clearance with high initial spleen and kidney uptake. Clearance of [99mTc]L8 from non-target organs, including kidney, was faster than for [99mTc]L11 or [99mTc]L18, resulting in increasing tumor/organ ratios at 5 h. [99mTc]L11 and [99mTc]L18 demonstrated higher tumor retention over time than did [99mTc]L8 at 16 h. Conclusions [99mTc]L8, [99mTc]L11 and [99mTc]L18 are promising candidates for imaging prostate cancer. Altering the chelator had significant impact on tumor uptake and pharmacokinetics