Biodistribution and radiation dosimetry of [18F]-JK-PSMA-7 as a novel prostate-specific membrane antigen-specific ligand for PET/CT imaging of prostate cancer

Aim We investigated the whole-body distribution and the radiation dosimetry of [18F]-JK-PSMA-7, a novel 18F-labeled PSMA-ligand for PET/CT imaging of prostate cancer. Methods Ten patients with prostate cancer and biochemical recurrence or radiologic evidence of metastatic diseases were examined with 329–384 MBq (mean 359 ± 17 MBq) [18F]-JK-PSMA-7. Eight sequential positron emission tomography (PET) scans were acquired from 20 min to 3 h after injection with IRB approval. The kidneys, liver, lungs, spleen, and salivary glands were segmented into volumes of interest using the QDOSE dosimetry software suite (ABX-CRO, Germany). Absorbed and effective dose were calculated using the ICRP-endorsed IDAC 1.0 package. The absorbed dose of the salivary glands was determined using the spherical model of OLINDA 1.1. PSMA-positive lesions were evaluated separately. Quantitative assessment of the uptake in suspicious lesions was performed by analysis of maximum (max) and peak SUV values. The gluteus maximus muscle (SUVmean) served as a reference region for the calculation of tumor-to-background ratios (TBR’s). Results Physiologic radiotracer accumulation was observed in the salivary and lacrimal glands, liver, spleen, and intestines, in a pattern resembling the distribution known from other PSMA-tracers with excretion via urinary and biliary pathways. The effective dose from [18F]-JK-PSMA-7 for the whole body was calculated to be 1.09E−02 mGy/MBq. The highest radiation dose was observed in the kidneys (1.76E−01 mGy/MBq), followed by liver (7.61E−02 mGy/MBq), salivary glands (4.68E−02 mGy/MBq), spleen (1.89E−02 mGy/MBq), and lungs (1.10E-2 mGy/MBq). No adverse effects of tracer injection were observed. Six out of ten patients were scored as PSMA-positive. A total of 18 suspicious lesions were analyzed, which included six bone lesions, nine lymph nodes, and three local lesions within the prostate fossa. The values for the SUVmax and SUVpeak in the PSMA-positive lesions increased until 60 min p.i. and remained at this intensity in the PET/CT scans until 140 min. In the period between 170 and 200 min after injection, a further significant increase in SUVmax and SUVpeak within the PSMA-positive lesions was observed. Conclusions The highest TBR of [18F]-JK-PSMA-7 was found 3 h after injection. From the kinetically collected data, it can be concluded that this trend may also continue in the further course. The start of the PET/CT acquisition should be chosen as late as possible. The high uptake in suspicious lesions in terms of absolute SUVmax and relative TBR values indicates potentially high sensitivity of the tracer for detection of prostate cancer manifestations.


Introduction
The use of PET tracers targeting the prostate-specific membrane antigen (PSMA) for imaging in patients with prostate cancer is gaining increasing interest and has shown great promise for improving the treatment of patients with prostate cancer [1].
A decisive breakthrough was achieved with low-molecular ligands that bind to the active center of the extracellular domain of prostate-specific membrane antigen [2,3]. It is therefore not surprising that great hopes are placed in improved diagnostics with PSMA-specific tracers for prostate cancer detection. In the meantime, a large number of small molecule PSMA ligands have been developed for use in PET imaging (e.g., [ 68 Ga]-PSMA-11 [4], [ 68 Ga]-PSMA I&T [5], [ 18 F]-DCFBC [6], [ 18 F]-DCFPyL [7][8][9], [ 18 F]-PSMA-1007 [10]). Most of these tracers have a fast renal clearance, which enables prompt PET diagnosis with a good lesion-to-background contrast. [ 18 F]-PSMA-1007 is characterized by a predominately hepatic-biliary excretion. Most clinical experience has been gained with [ 68 Ga]-PSMA-11. However, 68 Ga has several disadvantages with regard to decay properties and accessibility in comparison to 18 F-labeled PSMA compounds and is of limited availability due to its production in radionuclide generators. Furthermore, compared to 18 F (mean 0.65 MeV), the positron energy of 68 Ga is higher (mean 1.90 MeV), reducing the theoretical maximum achievable spatial resolution [11].
The first generation of 18 F-labeled PSMA-ligands, [ 18 F]-DCFBC, was described by Mease et al. [12]. Images obtained with [ 18 F]-DCFBC demonstrated a relatively high background activity [6]. This potential limitation has been addressed by the second generation of 18  [ 18 F]-PSMA-1007 offers the advantage that nuclides for diagnostics and therapy can be bound via a chelator [10]. For most of these PSMA-ligands, a complex manufacturing process is necessary [13][14][15][16][17]. The goal of this study was to investigate the whole-body distribution, radiation dosimetry, and safety of [ 18 F]-JK-PSMA-7 in patients with known prostate cancer. [ 18 F]-JK-PSMA-7 is a novel 18 F-labeled PSMA-ligand with similar properties to other renally excreted 18 F-labeled PSMA-ligands but with a "minimalistic light" manufacturing protocol as proposed by Richarz et al. [18] and by Neumaier et al. [19].

Patients
Between December 2017 and March 2018, 10 patients were subjected to [ 18 F]-JK-PSMA-7 PET/CT due to the progression of prostate cancer. Eight patients suffered from biochemical recurrence (BCR). Two patients had metastasized castration-resistant prostate cancer (mCRPC) and received androgen deprivation therapy (ADT).
PET/CT imaging was performed in accordance with the Institutional Review Board. All patients gave written informed consent to PET imaging and inclusion of their data in a retrospective analysis. All procedures were performed in compliance with the regulations of the local authorities responsible (District Administration of Cologne, Germany).

PET/CT acquisition and image reconstruction
All PET/CT scans were performed on a Siemens Biograph mCT (mCT 128 Flow Edge, Siemens, Knoxville, USA). In total, eight sequential whole-body PET scans were acquired from the base of the skull to mid-thigh. Patients were injected with 359 ± 17 MBq (4.25 ± 0.55 MBq/kg) of [ 18 F]-JK-PSMA-7 by a slow intravenous push. The PET acquisition was subdivided into two blocks and the patients into two groups of five according to the following scheme: in patient group no. 1, the first acquisition block started at 20 min p.i. and was repeated four times every 10 min up to 50 min p.i. After a break of 60 min, the second acquisition block started at 110 min p.i and was again repeated four times every 10 min up to 140 min p.i. During an intermission, the patients were allowed to leave the table to void as needed. For each acquisition block, a low-dose non-enhanced CT (120 kV, mA modulation, pitch 1.2, slice thickness 5.0 mm) was performed for attenuation correction. A similar procedure was used in patient group no. 2, the only difference being that the first PET scan was acquired 80 min p.i. and the last one 200 min p.i. All emission data were corrected for attenuation, randoms, scatter, and decay. Reconstruction was conducted with an ordered subset expectation maximization (OSEM) algorithm with 4 iterations and 12 subsets and Gauss-filtered to a transaxial resolution of 5 mm at full-width at half-maximum (FWHM).

Radiation dosimetry
Radiation dosimetry was performed using the QDOSE dosimetry software suite (ABX-CRO, Dresden, Germany). All PET and CT data sets were automatically co-registered. Non-target organs such as the kidneys, liver, spleen, lungs, and salivary gland were segmented into volumes of interest (VOI). Time activity curves (TAC) were calculated for the segmented organs. Curve fitting and integration was applied to all TACs to obtain the cumulated activity and residence time. The calculation of cumulated activity was divided into the following three sections: between time 0 and the first measuring point, a linear increase of the TAC was assumed. All measuring points were integrated numerically using trapezoidal approximation. From the last measuring point to infinity, a mono-exponential function was fitted over the last four measuring points and integrated. Whereas the absorbed dose to the salivary glands was determined using the spherical model from OLINDA/ EXM1.1 [21], the effective dose and absorbed partial and whole-body dose were calculated using the ICRP endorsed IDAC 1.0 package [22].

Biodistribution
The biodistribution of [ 18 F]-JK-PSMA-7 was quantified by maximum (max) and mean SUV values for all sequentially acquired PET images. The standardized uptake value (SUV) was defined by a circular region drawn around an area with focally increased uptake and automatically adapted to a three-dimensional VOI by software (syngo.via VB20A, Siemens, Erlangen, Germany). The kidneys, liver, spleen, lungs and salivary glands were evaluated with a VOI of 2-3 cm in diameter placed inside the organ parenchyma. PSMA-positive lesions were analyzed separately.
Blood radioactivity concentration was measured in the lumen of the left ventricle of the heart for all sequentially acquired PET images. Quantification was performed for the total blood volume, which was estimated by size, weight, and hematocrit [23]. For this purpose, mean values of the blood radioactivity concentration from both patient groups were determined.

PSMA-positive lesions
All PET/CT images were reviewed and analyzed on a syngo.via workstation (syngo.via VB20A Software, Siemens, Erlangen, Germany) by two experienced nuclear medicine physicians (both with 20 years' experience in PET scan reading, certificate for CT reading). The visual assessment of [ 18 F]-JK-PSMA-7 was considered to be positive if there was focal uptake above the mediastinal blood pool or the liver value. Spherical volumes of interest (VOIs) were manually drawn around areas with focally increased uptake. Quantitative assessment of the uptake in lesions was performed by analysis of maximum (max) and peak SUV values. SUV max is defined as the hottest voxel within a volume of interest. SUV peak computes the mean SUV within a 1-cm 3 sphere positioned within a VOI so as to maximize that mean. In doing so, voxel super-sampling is performed where the dimensions are halved until they are less than or equal to 0.5 mm on each axis [24]. Tumor-to-background ratios (TBRs) were calculated based on the following equation [25]:

Patient characteristics
The patients were on average 69 years old (range 52-76 years), with an average weight of 86 kg (range 74-100 kg). The average PSA value was 15.6 μg/L (range 0.51-130 μg/L). Nine patients had undergone radical prostatectomy, and one patient had external beam radiation therapy for primary treatment. Two patients received androgen deprivation therapy (ADT) within the last 6 months prior to the examination. Detailed patient characteristics are summarized in Table 1.

Biodistribution
Physiologic radiotracer accumulation was observed in the salivary and lacrimal glands, liver, spleen, and intestines, in a pattern resembling the distribution known from other PSMA tracers with excretion via urinary and biliary pathways. SUV max and SUV mean as well as their change over time in standard organs are presented in Fig. 1. Between 1 h and 3 h p.i., the uptake in the liver demonstrated an increase in SUV max and SUV mean of around 69%, whereas the uptake in the other standard organs showed a decrease in SUV max and SUV mean , amounting to − 37% for the kidneys, − 41% for the spleen, − 45% for the lungs, and − 14% for the salivary glands (mean values).
As can be seen in Fig. 2, fast excretion via the blood is evident. From the exponential fit of the TAC, an average halflife of the blood activity concentration of 74 min can be calculated. The whole blood pool contained in mean 13%, 8%, and 4% of the injected activity at 1 h, 2 h, and 3 h p.i., respectively. These initial clinical data are in good agreement with the preclinical data collected in rats [20].  Table 2. For comparison, Table 3 presents the corresponding absorbed doses and residence times for other 18

Statistical comparison with other PSMA ligands
There was no statistically significant difference between the residence times of    n.a. not available, SD standard deviation *The residence time for the whole-body was the same for all three patients [10] Quantitative analysis of PSMA-positive lesions All PSMA-positive lesions showed an increased uptake over time, although significant differences emerged between the two patient groups. In patient group no. 1, the SUV max and SUV peak values increase slowly over time and reach an almost stable plateau 100 min after injection. In patient group no. 2, on the other hand, the SUVmax and SUV peak values continue to rise significantly. These differences in the time courses of SUV max and SUV peak are reflected in corresponding values for the TBR. Thus, between 100 and 140 min p.i., the mean TBR increased by 50%, whereas between 140 and 200 min p.i., the mean TBR increased by 78%. Figure 3 shows the time course of the SUV max , SUV peak , and TBR in PSMA-positive lesions. In addition, Fig. 4 shows the images of two patients, one from patient group no. 1 and one from patient group no 2.

Adverse events
All patients tolerated the examination well. No drug-related pharmacological effects or physiologic responses were observed. None of the patients reported any adverse events or side-effects at the time, when the PETresults were discussed with the patient or some weeks later, when the therapeutic consequences were discussed by telephone counseling.

Verification
Five out of the 6 patients with PSMA-positive lesions showed a decreased PSA level after radiotherapy of the PSMA-positive lymph nodes or after salvage radiotherapy of the PSMA-positive lesions within the prostate fossa. One patient had multiple PSMA-positive lymph nodes and skeletal lesions, which were also visible on the CT scan. Two out of the 4 patients with a PSMA-negative PET result had a stable PSA level after 6 to 8 months without any therapy. One patient received salvage radiotherapy and the PSA level decreased. One patient developed osteosclerotic bone metastases after 9 months, then visible on the CT scan, but again PSMA-negative with [ 68 Ga]-PSMA-11.

Discussion
Ten patients were examined with [ 18 F]-JK-PSMA-7. In summary, the observation of patients with the novel tracer can be summarized as follows. The mean effective dose was comparable to that of other 18 F-labeled PSMA ligands. Furthermore, the preserved organ doses were within the same order of magnitude as other 18 F-labeled PSMA ligands. One problem with the comparison of organ doses is that in previous studies, the organ masses have been determined differently. In some cases, the masses were determined individually for each patient using CT images [10] while elsewhere reference organ masses according to ICRP were used [7]. A comparison of the different tracers on the basis of the residence times and thus independent of mass is therefore much more conclusive. Regarding the tracer residence times in various organ systems, no significant difference was found between [ 18 F]-JK-PSMA-7 and [ 18 F]-PSMA-1007. Significant increases were found for the liver in comparison to DCFBC (28%, p = 0.002) and DCFPyL (47%, p = 0.034). It should be noted here that the mean values from the other studies are based on very small cohorts (usually only three to five patients). In our study, the mean values are based on ten examined patients.
[ 18 F]-JK-PSMA-7 showed a fast excretion via the blood in a similar order of magnitude to [ 18 F]-DCFPyL. Zlatopolskiy et al. [20] were able to show that the blood protein binding of [ 18 F]-PSMA-1007 and [ 68 Ga]-PSMA-11 was significantly higher compared to [ 18 F]-JK-PSMA-7. High blood protein binding may delay the excretion of the tracer resulting in lower accumulation in kidneys and bladder. This could be advantageous for detecting PCa metastases adjacent to urethra and bladder, while a faster excretion would favorably affect the background enrichment. i. and corresponding values for the SUV max , SUV peak , and TBR of a suspicious retroperitoneal lymph node (arrow). Here, we have quantified the middle lymph node from a PSMA-positive lymph node chain A major strength of this study is that we investigated the temporal course of SUV values not only for organs but also for 18 F-PSMA-positive lesions over a long period of time. The values for SUV max and SUV peak in the PSMA-positive lesions increased for up to 60 min p.i. and remained at this intensity in the subsequent PET/CT scans up to 140 min p.i. In the period between 170 and 200 min after injection, further significant increases in SUV max and SUV peak were seen in PSMApositive lesions. From this data, it can be concluded that a late acquisition window, even up to 3 h after injection, may be favorable for this tracer. This also confirms the observations made from evaluation of Lu 177 -PSMA therapies. The tracer uptake in PSMA-positive lesions was found to increase up to 24 h after injection, in contrast to uptake in non-target organs, which mainly peaked on the day of treatment, and declined thereafter [26]. Therefore, there might be a clear advantage compared to [ 68 Ga]-PSMA-11. The direct comparison of [18F]-JK-PSMA-7 with [ 68 Ga]-PSMA-11 and other 18 F-labeled PSMA-ligands will be the subject of another work by our department [27].
One limitation of this study is that [ 18 F]-JK-PSMA-7 was not tested on healthy volunteers. But there is no reason to assume that normal organs, when free of lesions, have a different tracer uptake in healthy men compared to patients. For [ 18 F]-DCFPyL, the dosimetry in normal organs was proven to be assessed independently of tumor presence [7].

Conclusion
The radiation dose from [ 18 F]-JK-PSMA-7 was similar to that delivered by other 18 F-labeled PSMA-ligands. The highest TBR was found 3 h after injection. From the kinetically collected data, it can be concluded that this trend may also continue in the further course. The start for the PET/CT acquisition should be chosen as late as possible. The high uptake in suspicious lesions in terms of absolute SUV max and relative TBR values indicates potentially high sensitivity of the tracer for the detection of prostate cancer manifestations. In order to evaluate the potential sensitivity and optimized pharmacokinetics of [ 18 F]-JK-PSMA-7, a larger prospective and comparative study is ongoing.