Abstract
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Objectives Previously we demonstrated successful radiometal or fluorescence imaging in experimental models of prostate cancer using urea-based inhibitors of PSMA. A variety of imaging moieties and linkers produced compounds with different lipophilicities but all displayed tumor targeting and favorable pharmacokinetics. Here we report a dual modality SPECT/NIRF imaging agent, [111In]SRVII23, which utilizes the Lys-urea-Glu scaffold.
Methods SRVII23 was synthesized with a DOTA chelator for 111In labeling (SPECT) and with IRDye800CW dye for NIRF imaging. Specific activities ranged from 45.5 - 325 GBq/µmol. Ki values for SRVII23 and [113/115In]SRVII23 were measured using a fluorescence-based competitive PSMA inhibition assay. PSMA binding was evaluated in vitro by fluorescence imaging and in vivo by SPECT/CT, optical imaging and biodistribution studies using SCID mice bearing a PSMA+ PC-3 PIP and a PSMA- PC-3 flu tumor in opposite flanks.
Results Ki values for SRVII23 and [113/115In]SRVII23 were 0.46 and 1.24 nM, respectively. SRVII23 and [113/115In]SRVII23 demonstrated PSMA-mediated uptake in vitro by fluorescence microscopy. [111In]SRVII23 demonstrated significant uptake within PSMA+ PC-3 PIP tumor, with little uptake in PSMA- PC-3 flu tumor, which persisted for at least 24 h (13.91 ± 1.94, 13.26 ± 2.44, 16.37 ± 0.90, 14.63 ± 1.26 (SEM) %ID/g at 1, 3, 5 and 24 h, respectively). Except for kidney, spleen and bladder, no significant non-target uptake was found. The PSMA binding specificity of [111In]SRVII23 was further confirmed by effective blocking in PSMA+ PC-3 PIP tumor and kidney. We also performed sequential SPECT/NIRF imaging with the same injection, which was at the radiotracer level (1 mCi). NIRF imaging of PSMA+ PC-3 PIP tumor could be demonstrated at concentrations down to 0.1 nM at 48 h post-injection.
Conclusions [111In]SRVII23 enables sequential, dual modality SPECT/NIRF imaging of experimental prostate cancer at radiotracer levels in a single injection