PSMA targeted SPECT imaging biomarker to detect local and metastatic prostate cancer (PCa): Phase I studies with ^99mTc-MIP-1404

Objectives We have previously reported the evaluation of I-123 and Tc-99m labeled small molecules that bind with high affinity to the enzymatic domain of prostate specific membrane antigen (PSMA) via its glutamate carboxy-peptidase or NAALADASE activity. A critical challenge in imaging PCa is to visualize recurrent or metastatic disease early, as well as to differentiate clinically significant from silent or indolent disease. We present here the results from two phase I studies with ^99mTc-MIP-1404 (Tc-MIP-1404) in patients with metastatic PCa, and in patients scheduled for prostatectomy (PT).

Methods Tc-MIP-1404 was prepared by reacting the precursor MIP-1404 (0.1 mg) with 200 mCi of ^99mTc-tricarbonyl reagent at 100 ^oC for 60 min. Specific activity was >40 GBq/µmole. Two phase 1 studies were conducted in patients with radiographic evidence of metastatic PCa (n=6) and in patients scheduled for PT (n=10) and pelvic lymph node dissection (PLND). Following injection of 20 mCi of Tc-MIP-1404, serial planar whole body and SPECT images were obtained over a 4 hr period.

Results Tc-MIP-1404 cleared rapidly from the circulation, showed minimal urinary activity, but moderate (15-20%) liver and kidney uptake. In men with metastatic PCa, Tc-MIP-1404 rapidly localized to lesions in lymph nodes and bone as early as 1 hr. SPECT/CT images demonstrated excellent lesion contrast. In most patients, more lesions were demonstrated with Tc-MIP-1404 than bone scan. In all subjects with Gleason score (GS) >7, Tc-MIP-1404 SPECT clearly identified the PCa foci confirmed by histopathology and PSMA staining.

Conclusions The small molecule PSMA inhibitor, Tc-MIP-1404 rapidly detects primary and metastatic PCa with high specificity. The uptake in the lesions correlate with both GS and PSMA expression. A multi-center, international phase II study with Tc-MIP-1404 in patients scheduled for prostatectomy is in progress.