Single-Center Comparison of [64Cu]-DOTAGA-PSMA and [18F]-PSMA PET–CT for Imaging Prostate Cancer

Introduction: the diagnostic performance of [64Cu]-DOTAGA-PSMA PET–CT imaging was compared retrospectively to [18F]-PSMA PET–CT in prostate cancer patients with recurrent disease and in the primary staging of selected patients with advanced local and possible metastatic disease. Methods: We retrospectively selected a total of 100 patients, who were consecutively examined in our department, with biochemical recurrence after radical prostatectomy or who had progressive local and possible metastatic disease in the last 3 months prior to this investigation. All patients were examined with a dedicated PET–CT scanner (Biograph; Siemens Healthineers). A total of 250 MBq (3.5 MBq per kg bodyweight, range 230–290 MBq) of [64Cu]-DOTAGA-PSMA or [18-F]-PSMA was applied intravenously. PET images were performed 1 h post-injection (skull base to mid-thigh). The maximum standardized uptake values (SUVmax) of PSMA-positive lesions and the mean standardized uptake value (SUVmean) of the right liver lobe were measured. Results: All but 9/50 of the patients (18%; PSA range: 0.01–0.7 µg/L) studied with [64Cu]-DOTAGA-PSMA and 6/50 of the ones (12%; PSA range: 0.01–4.2) studied with [18F]-PSMA had at least one positive PSMA lesion shown by PET–CT. The total number of lesions was higher with [64Cu]-DOTAGA-PSMA (209 vs. 191); however, the median number of lesions was one for [64Cu]-DOTAGA-PSMA and two for [18F]-PSMA. Interestingly, the median SUVmean of the right liver lobe was slightly higher for [18F]-PSMA (11.8 vs. 8.9). Conclusions: [64Cu]-DOTAGA-PSMA and [18F]-PSMA have comparable detection rates for the assessment of residual disease in patients with recurrent or primary progressive prostate cancer. The uptake in the liver is moderately different, and therefore at least the SUVs of the lesions in both studies would not be comparable.


Introduction
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies in men, with a total of 1,414,259 new cases and an estimated 375,000 deaths worldwide in 2020 [1]. The treatment management of PCa depends on the site and extent of disease (local/nodal vs. systemic disease) [2]. Even though several novel pharmacologic drugs have been introduced to the therapeutic armamentarium against metastatic PCa, advanced disease still represents a fatal condition for these patients [3]. For proper staging, imaging modalities such as CT, multiparametric MRI and bone scans are recommended in patients with intermediate risk and localized or locally advanced high-risk PCa [2]. In cases of biochemical recurrence (BCR) after radical prostatectomy or radiation therapy, functional PET-CT imaging using radiolabeled choline or prostate-specific membrane antigen (PSMA) ligands have been introduced [4]. PSMA is a transmembrane protein that is expressed in normal and neoplastic prostate tissue, with a structure composed of a 707-amino-acid external portion, a 19-amino-acid internal portion and a 24-amino-acid transmembrane portion [5]. In light of its specificity, PSMA has been selected as the biological target of a number of radiolabeled small molecules, such as  [7]. Previous studies have shown a high diagnostic performance of [ 68 Ga]-labeled urea-based PSMA in the detection of lymph node metastases in BCR patients [8]. Additionally, PSMA ligands in molecular PET imaging provide a higher tumor detection rate as compared to choline ligands in patients with BCR, especially in cases of very low PSA levels [9].
PSMA-PET has become a highly accurate staging tool in multiple settings in clinical routine, although its exact uses in clinical practice remain to be determined. We use it in our department for staging treatment-naïve locally advanced disease as well as recurrent and metastatic disease.  (11). DOTA and NODAGA chelators form stable complexes with Cu and have been clinically used [11]. Another PSMA ligand which was introduced recently is 64 Cu-PSMA-BCH, which was shown to have a high stability in vivo with a lower uptake in the liver than 64 Cu-PSMA-617 [12]. PSMA I&T labeled with 64 Cu also showed the feasibility of PET imaging through in vitro and in vivo studies [13]. In patients with low PSA values, a better performance was observed for 64 Cu-PSMA-617 PET/CT compared to 18 F-choline PET/CT in restaging after BCR [14].
In contrast, [ 18 F] has been well established as a diagnostic radionuclide due to its physical and nuclear characteristics: a high positron decay ratio (97%), a relatively short half-life (109.7 min) and low positron energy (Emax = 0.63 MeV) [15].
The aim of our study is to evaluate the uptake behavior of [ 64 Cu]-DOTAGA-PSMA with DOTAGA as a possible stable chelator compared to [ 18 F]-PSMA PET-CT in a routine clinical setting in PCa patients.

Methods
We selected retrospectively a total number of 100 patients (50 examined with [ 64 Cu]-DOTAGA-PSMA and 50 with [ 18 F]-PSMA PET-CT), who were consecutively examined in our department, with biochemical recurrence after radical prostatectomy or had progressive local disease in the last 3 months and were scheduled for either radiation or systemic therapy. Routinely, we perform, due to logistic reasons,

Statistical Analysis
For the two patient cohorts the median values of age, PSA value at time of PET-CT, the SUVmean of the right liver lobe and the SUVmax of the lesion with the highest uptake as well as the total number of lesions are presented in Table 1. Additionally, we performed a Student's t-test to identify significant differences between the two patient cohorts.

Results
Patient baseline characteristics are listed in Table 1. The two patient cohorts were comparable, as we found no significant differences with regard to age range, PSA values at the time of examination and the SUVmax of the hottest lesion (Table 2). In Figures 1 and 2 we show one representable patient case for each cohort.

Discussion
The results in this study in regard to negative findings are superior to our previous study with [ 64 Cu]-NODAG-PSMA, where 20.8% of the patients did not show any lesions in PET scans [11]. However, the previous study was performed on a stand-alone PET scan (without CT), and therefore this comparison is of limited significance.
The total number of lesions was higher with [ 64 Cu]-DOTAGA-PSMA (209 vs. 191); however, the median value of lesions was one for [ 64 Cu]-DOTAGA-PSMA and two for [ 18 F]-PSMA, and thus failed to be statistically significant (p = 0.07). Interestingly, the median value of SUVmean of the right liver lobe was significantly higher with [ 18 F]-PSMA (p < 0.05). We measure and mention this parameter in our PET reports in order to compare different studies at different time points, or if they are performed with different radiopharmaceuticals.
In our study, we found comparable results between [ 64 Cu]-DOTAGA-PSMA and [ 18 F]-PSMA in our patients. The performance of both radiopharmaceuticals were comparable and better than our previously published results with [ 64 Cu]-NODAGA-PSMA PET, with the limitation that the latter was performed on a stand-alone PET scanner [11]. This suggests in vivo stability of [ 64 Cu]-DOTAGA-PSMA as it could be shown for [ 64 Cu]-NODAGA-PSMA in our previous study [11]. Additionally, as mentioned elsewhere, [ 64 Cu] as a radionuclide for PSMA shows more favorable physical characteristics, such as a longer halflife of 12.7 h and a small positron range with increased spatial resolution [16]. Interestingly, in a study, 64 Cu-PSMA-617-PET was demonstrated to be feasible for imaging prostate cancer for both the primary tumor site and metastases, whereas later imaging 2-22 h post-injection showed no additional, clinically relevant benefit compared to the early scans [17].
It was not the aim of this study to look for any impact of Gleason score (GS) on PET results; however, in a previous publication we could not find any correlation between GS and PSMA-PET [11]. Furthermore, downregulation of PSMA expression due to androgen deprivation therapy (ADT) might have an influence on size reduction in tumors [18], and some of our patients were under ADT treatment. Additionally, there are published limitations of [ 68 Ga]-PSMA with a very low expression of PSMA in dedifferentiated tumors, the absence of a relationship between [ 68 Ga]-PSMA uptake and Gleason score in addition to the downregulation of PSMA expression by ADT [18]. The introduction of copper as a ligand in primary staging and in recurrent disease demonstrates an excellent resolution of the detected lesions with a very high lesion-to-background contrast. Grubmüller  The limitations of this study are the retrospective nature, lack of intra-individual comparison, that the histopathology of all lesions was not obtainable in our patients and that only the number of lesions were analyzed. However, PCa was proven by biopsy or histopathology. Informed Consent Statement: Formal consent was obtained from all patients prior to examination.

Data Availability Statement:
The above-mentioned data were acquired from our in-house PET-CT center. No other publicly archived dataset was analyzed.

Conflicts of Interest:
The authors declare no conflict of interest.