^99mTc-MIP-1340, a small molecule inhibitor of PSMA for molecular imaging of prostate cancer

Objectives Prostate specific membrane antigen (PSMA) is upregulated in prostate cancer. MIP-1340 was selected as a lead candidate from a library of small molecule inhibitors of PSMA and evaluated for molecular imaging of prostate cancer.

Methods Re(CO)₃-MIP-1340, (7S,14S,18S)-7-amino-1-(1-(carboxymethyl)-1H-imidazol-2-yl)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylic acid, a PSMA inhibitor derived from the Glu-urea-Lys pharmacophore incorporating a novel polar tridentate imidazole chelator was synthesized and evaluated in a competitive binding assay against 2-{3-[1-carboxy-5-(4-[¹²³I]iodo-benzylamino)-pentyl]-ureido}-pentanedioic acid. ^99mTc-MIP-1340 was examined for saturation binding and cellular internalization on PSMA(+) LNCaP cells. Tissue distribution in LNCaP xenograft models with and without cold competition and µSPECT imaging were also performed.

Results MIP-1340 has high affinity for PSMA (18 nM IC₅₀ by competition binding; 4.4 nM K_d by saturation binding) and excellent specificity (competition in LNCaP cells with PMPA and lack of binding to PSMA(-) PC3 cells). Time and temperature dependent increase in acid-insensitive cell association of MIP-1340 indicated internalization. In vivo, ^99mTc-MIP-1340 achieved 12% ID/g in PSMA(+) tumors with tumor:blood >20:1 and tumor:muscle >40:1 at 1 h. Co-injection with 0.1-1000 μg/kg cold MIP-1340 reduced in vivo tumor uptake in a dose dependent fashion. µSPECT imaging corroborated localization to LNCaP tumors and kidney but not non-target tissues.

Conclusions ^99mTc-MIP-1340 binds specifically and with high affinity to PSMA and accumulates in human prostate cancer xenografts with an indicator dilution consistent with saturatable binding. The novel polar ^99mTc-chelate provides an attractive pharmacokinetic profile for imaging prostate cancer metastases using SPECT.

Research Support R43 EB004253-0