The clinical application of PET imaging with the 68Ga-labeled PSMA radioligands, such as [68Ga]Ga-PSMA-11 and [68Ga]Ga-PSMA-617, has been regarded as a revolutionary breakthrough in the diagnosis of PCa [20]. In the past few years, PSMA-targeting radiotracers has been structurally modified with the goal to achieve improved specificity and sensitivity for clinical applications [21].
In our study, [68Ga]Ga-P16-093 PET/CT exhibited remarkably higher SUV values of tumor lesions and TBR, better tumor detection ability, as well as lower blood pool and bladder accumulation than those observed by [68Ga]Ga-PSMA-617 scan. Importantly, we performed this research by comparing the two agents in the same patients, rather than conducting group analysis. And both PET/CT scans were randomly performed in two successive days. Obviously, given the nature of PCa progression, there was no significant variation in PCa lesions within such a short period of time. So, findings of this prospective head-to-head comparison study are credible.
As expected, the biodistribution patterns in normal tissues of [68Ga]Ga-P16-093 were similar to [68Ga]Ga-PSMA-617 and other small molecular weight PSMA-targeting radiotracers [22–25]. But there were substantial differences between [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-617. We will emphasize and discuss the results of this study in detail to further confirm the advantages of [68Ga]Ga-P16-093 over [68Ga]Ga-PSMA-617 as the following.
First and foremost, [68Ga]Ga-P16-093 showed statistically significant higher tracer uptakes (higher SUVmax) and a superior satisfactory detection ability of tumor lesions than [68Ga]Ga-PSMA-617. Particularly for the recurrent PCa patients, NCCN guidelines recommend that confirming metastases was a key factor for PCa patients with BCR and CRPC, as this determined their therapeutic schedules [26]. Nevertheless, accurate detection of lesion is still challenging due to its slowly progressive disease occurring and multiple treatment options. There were a number of prospective and retrospective studies using different imaging agents to compare the detection ability of biochemical recurrent and progressive PCa patients, with the purpose of finding a more appropriate imaging modality [27–31]. In our study, the better detection ability of tumor lesions by [68Ga]Ga-P16-093 is a significant advantage over [68Ga]Ga-PSMA-617, which might benefit the subsequent management of patients.
Secondly, [68Ga]Ga-P16-093 exhibited increased blood clearance rate than [68Ga]Ga-PSMA-617, which is also an important aspect to enhance the detection ability. In this study, the positive finding of [68Ga]Ga-P16-093 in mediastinal lymph nodes compared with [68Ga]Ga-PSMA-617 (Fig. 4) had well demonstrated this superiority. Furthermore, [68Ga]Ga-P16-093 showed lower bladder accumulation in comparation with [68Ga]Ga-PSMA-617, which was also of paramount importance in the diagnosis of recurrent prostate cancer. Low bladder activity was beneficial to identify localized lesions in close anatomical relation to the urinary bladder as recurrence PCa was most frequently associated with pelvic lymph node, which was previously demonstrated in a prospective study [32]. Although there were no lesions found around the bladder in our study, this showed a special advantage of [68Ga]Ga-P16-093 over [68Ga]Ga-PSMA-617 for detection of lesions in the pelvic area. However, it should be noted that the kidneys was still the critical organ, since the slightly higher radioactive retention for [68Ga]Ga-P16-093 than [68Ga]Ga-PSMA-617, which was consistent with previous research [14].
Thirdly, the main difference between the two drugs was that [68Ga]Ga-P16-093 demonstrated higher hepatobiliary excretion and parotid gland cumulated activity value than [68Ga]Ga-PSMA-617, as shown in the MIP images and TACs, which were statistically significant as exhibited in the Results (Fig. 3). This is a phenomenon worthy of attention, in general, we prefer a lower uptake in the liver so as not to affect the detection of liver metastases. High liver uptake could, however, be a less significant factor for using [68Ga]Ga-P16-093 imaging in PCa, because it is uncommon to have liver metastasis in these patients.
As for our dPET/CT studies, we also observed that quite a few of PCa lesions presented with visible contrast at 4 min after the injection of imaging agents. Whereas, the blood pool background accumulation was relatively high at this time point, it was not the optimal time point of imaging. Although previous studies have demonstrated that early dynamic scan in PET/CT can reliably identify pathologic tracer uptake in PC lesions from physiologic accumulation in the urinary bladder [33, 34]. Our early dynamic PET/CT acquisition did not detect more PCa lesions, which indicated that early dynamic imaging may be of little use due to the shortcomings of technically demanding and time-consuming [35]. Of course, further analyses are needed to confirm this result. EANM and SNMMI procedure guideline suggested a 60-min interval (range 50–100 min) was appropriate for uptake time [36]. In our study, the images at 20 min on [68Ga]Ga-P16-093 PET/CT exhibited roughly equivalent tracer uptakes of tumor lesions and higher TBR to that at 60 min on [68Ga]Ga-PSMA-617 PET/CT. We propose that [68Ga]Ga-P16-093 PET/CT allows a more flexible imaging time, which greatly increases the practicability and alleviate concerns with regard to necessary coordination of patient activities. So, we suggest that a 20–60 min interval for uptake time for [68Ga]Ga-P16-093 PET/CT scan may be appropriate.
There were some limitations in our study. Firstly, the studied cohort was relatively small. Nevertheless, it was surprising that there were statistically significant differences in many aspects, such as tumor uptake, detection ability, in this small sample. The second limitation was the lack of histological confirmation of both the [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-617 avid focal lesions in cases of recurrent PCa. Whereas, quite a few studies had confirmed the high correlation between immunohistochemical findings and PSMA PET/CT imaging in PCa [28, 37]. Therefore, the results of PET/CT are reliable and consistent with pathological examination.
In the past ten years, precision medicine based on PSMA-targeting theranostic agents has created a dramatic shift in the practice of nuclear medicine. Significant impact of PSMA PET imaging in diagnosis and management of prostate cancer at different stages is well-recognized [20, 38]. Recently, [68Ga]Ga-PSMA-11 [39, 40] and [18F]PYL (Pylarify; piflufolastat F 18) [41] have received approval by Food and Drug Administration (FDA), and PSMA PET imaging is now becoming an important part of standard clinical practice for diagnosis and treatment of prostate cancers all over the world. [68Ga]Ga-PSMA-11 and [68Ga]Ga-PSMA-617 are two of the most widely used 68Ga-labeled imaging agents for the diagnosis of prostate cancer. Based on numerous advantages of [68Ga]Ga-P16-093, described herein, it could be an excellent alternative agent, which can be prepared readily in high yield and purity at local hospitals. In the past three years, [68Ga]Ga-P16-093 was under clinical studies in the Indiana University and University of Pennsylvania (IND #133222). We hope that [68Ga]Ga-P16-093, if it is successfully tested and approved by the local authority, could serve the un-met clinical need worldwide.