Prostate cancer has an increasing incidence in the world so that there is a need of cost-effective PSMA imaging and therapy [4, 14]. Besides PSMA PET tracers, several [99mTc]Tc-labeled PSMA ligands have been developed in recent years [15]. Contrary to PET, gamma scanners are broadly available throughout the world suggesting the usefulness of compatible radioligands [6, 16].

The first human data with [99mTc]Tc-MIP-1404 and [99mTc]Tc-MIP-1405 showed very promising results [6, 17]. In 2017, Ferro-Flores et al. introduced [99mTc]Tc-EDDA/HYNIC-iPSMA which offers a rapid blood clearance, the ability to detect prostate cancer, as well as its metastases, and has mainly kidney elimination with less liver uptake than [99mTc]Tc-MIP-1404 [18]. Further investigations with [99mTc]Tc-EDDA/HYNIC-iPSMA demonstrated high detection rates for PSMA positive lesions, especially in the setting of biochemically recurrence of prostate cancer but a lower sensitivity compared with PET PSMA tracer [4, 19]. The main advantage of the new 99mTc-labeled tracer group is the detection of PSMA positive lesions for planning radio-ligand therapy, for instance, with [177Lu]Lu-PSMA-617 [8] (Fig. 5). A specific radio-ligand therapy of prostate cancer can only be performed in presence of PSMA-positive phenotype of tumor lesions [20]. The sensitivity of PSMA imaging plays a subordinate role in this context, rather, the diagnostic and therapeutic compounds should be as similar as possible to predict kinetics and uptake of the latter [7, 8].

Eighty-one-year-old male patient. This presents an extended prostate cancer undergoing a phenotyping for specific radio-ligand therapy with PSMA. a [99mTc]Tc-MDP uptake in whole body projections, b [99mTc]Tc-PSMA-GCK01 uptake in whole body projections, and c [177Lu]Lu-PSMA-617 uptake in whole body projections. [99mTc]Tc-PSMA-GCK01 reveals more lesions compared with [99mTc]Tc-MDP. [99mTc]Tc-PSMA-GCK01 uptake correlates very well with therapeutic biodistribution

The novel PSMA ligand [99mTc]Tc-PSMA-GCK01 was optimized to provide a suitable basis for both 99mTc- and 188Re-labeling, thus, providing a seamless PSMA-targeted theranostic tandem [13]. In this investigation we have analyzed the biodistribution of the diagnostic [99mTc]Tc-PSMA-GCK01 in organs with physiologic PSMA-uptake and in metastases to assess the appropriateness for imaging, especially in comparison with [99mTc]Tc-EDDA/HYNIC-iPSMA. The ROI-based analysis showed equal tracer uptake in salivary glands and background with [99mTc]Tc-PSMA-GCK01 and [99mTc]Tc-EDDA/HYNIC-iPSMA, respectively.

This observation is also in agreement with the results from our in silico docking study, revealing only minimal differences in the conformations of both molecules in the PSMA binding pocket, and, thus, only a minimal difference in the docking score of approx. 1.0 kcal/mol. Considering the high structural similarity of both PSMA ligands, differing only in their chelator moiety and slightly in the linker region, this explains our earlier findings of a slightly higher affinity of [99mTc]Tc-PSMA-GCK01 (Ki = 26 nm) toward PSMA when compared to [99mTc]Tc-EDDA/HYNIC-iPSMA (Ki = 38 nm) [13].

In the practical setting, both tracers had a relevant uptake in the kidneys and the liver. But in the case of [99mTc]Tc-PSMA-GCK01, a minor shift of the uptake to the liver parenchyma was observed. This behavior is particularly interesting because in mice only minimal liver uptake was previously described [13]. Differences in biodistribution between preclinical data and in humans have already been reported for PSMA tracers [21]. Vallabhajosula et al. found a very high liver uptake for [99mTc]Tc-MIP-1404 contrary to preclinical data [17]. [99mTc]Tc-EDDA/HYNIC-iPSMA was optimized for rapid blood clearance; however, more activity is cleared by the kidneys to the bladder [18]. The rapid blood clearance of [99mTc]Tc-EDDA/HYNIC-iPSMA is maintained with [99mTc]Tc-PSMA-GCK01 but the slight predominant hepatobiliary route of excretion of [99mTc]Tc-PSMA-GCK01 might allow a better diagnostic performance of local relapse or perivesical lymph node metastasis [22] since tracer retention in the bladder might complicate the proper discrimination of perivesical lesions. Further, the slight predominant hepatobiliary excretion could be particularly beneficial when the ligand is labeled with 188Re in regard to radioligand therapy in terms of nephrotoxicity.

We have also compared the uptake of both tracers in the metastases. The analysis of tumor-to-background ratio presented equal results of [99mTc]Tc-PSMA-GCK01 and [99mTc]Tc-EDDA/HYNIC-iPSMA on the planar whole body projections. Thus, the slight preference for hepatobiliary clearance of [99mTc]Tc-PSMA-GCK01 does not have a negative effect on the imaging properties of tumor lesions and rather offers an optimized biodistribution regarding radioligand therapy, as mentioned above.

The main advantage of [99mTc]Tc-PSMA-GCK01 over [99mTc]Tc-EDDA/HYNIC-iPSMA is its utilization for theranostic purposes by 188Re labeling [13, 15]. This ensures the correlation between pre-therapeutic and therapeutic distribution and is expected to have a direct impact on the clinical routine.

Although PSMA PET radioligands and Tc-labeled PSMA SPECT tracers use the same target structure, there are differences in sensitivity [19] and lesion-to-liver ratio. The latter is important in case of eligibility for [177Lu]Lu-PSMA therapy and needs to be adjusted if 99mTc labeled tracers are used for the pre-therapeutic diagnostic [8, 23]. The tracer PSMA-GCK01 labeled with 99mTc-/188Re-theranostic tandem could solve this problem [13] without negatively affecting the biodistribution and general imaging characteristics compared with [99mTc]Tc-EDDA/HYNIC-iPSMA.