Preclinical application of a dual-tracer SPECT approach with [111In]In-PSMA-I&T and [99mTc]Tc-DPD for improved diagnosis of prostate cancer

Background Many high-risk prostate cancer (PCa) patients need to undergo 99m Tc-based bone scintigraphy as part of conventional diagnostics to assess metastasis to the bone. Besides, targeting the prostate-specific membrane antigen (PSMA) has proven to be very effective for theranostic approaches in PCa in recent years. Therefore, we recognized the high clinical potential of a dual-tracer approach, simultaneously targeting PSMA-expressing lesions and PSMA-negative bone anomalies. In a preclinical PCa model, we aimed at concurrent administration and dual-isotope single-photon emission computed tomography (SPECT) of two radiotracers labeled either with Indium-111 ( 111 In) or Technetium-99m ( 99m Tc). Separate depiction of the signals should illustrate the different biodistribution of [ 111 In]In-PSMA-I&T and 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ([ 99m Tc]Tc-DPD) in the animal. Results Temporally parallel radiosyntheses and analysis of [ 111 In]In-PSMA-I&T and [ 99m Tc]Tc-DPD were successfully established. Co-incubation studies were conducted with the radioligand stock solutions as well as in vitro experiments using LNCaP cells. LNCaP xenograft-bearing CB17-SCID mice were injected almost simultaneously with [ 111 In]In-PSMA-I&T and [ 99m Tc]Tc-DPD and scanned at different time points after injection (2–3 h and 23 h p.i.) on a Siemens Inveon µ SPECT/CT. Thereafter, mice were subjected to biodistribution studies. Co-incubation experiments revealed no mutual detrimental effects on radioligand purities. In vitro studies confirmed that the presence of DPD has no influence on [ 111 In]In-PSMA-I&T binding and internalization into PSMA-expressing LNCaP cells. By application of three different acquisition windows ( 99m Tc: 126–154 keV, 111 In: 221–269 keV, open: 80 - 270 keV) radionuclide-specific uptake could be observed and distinguished in the PSMA-expressing xenografts ([ 111 In]In-PSMA-I&T) and in the bones ([ 99m Tc]Tc-DPD). Biodistribution data corroborated these results. Conclusions Dual-tracer SPECT imaging of PSMA-positive xenografts and PSMA-negative bone structures with [ 111 In]In-PSMA-I&T and [ 99m Tc]Tc-DPD, respectively, was successfully realized in this preclinical approach. The positive results of this proof-of-concept study indicate a potentially prompt and successful transfer to clinical settings in which PSMA − bone lesions can be identified besides the PSMA + primary tumor and metastases in a single SPECT/CT scan. This in turn could reduce scan time, CT dose and costs per patient, and provide important insights into tumor biology and improve stratification and treatment of PCa patients.