PET imaging with the prostate-specific membrane antigen (PSMA)-targeted radioligand (68)Ga-PSMA-11 is regarded as a significant step forward in the diagnosis of prostate cancer (PCa). More recently, ...a PSMA ligand was developed that can be labeled with (68)Ga, (111)In, (177)Lu, and (90)Y. This ligand, named PSMA-617, therefore enables both diagnosis and therapy of PCa. The aims of this evaluation were to clinically investigate the distribution of (68)Ga-PSMA-617 in normal tissues and in PCa lesions as well as to evaluate the radiation exposure by the radioligand in PET imaging.
Nineteen patients, most of them with recurrent PCa, were referred for (68)Ga-PSMA-617 PET/CT. The quantitative assessment of tracer uptake of several organs and of 53 representative tumor lesions was performed in 15 patients at 1 and 3 h after injection. In 4 additional patients, the same procedure was conducted at 5 min, 1 h, 2 h, 3 h, 4 h, and 5 h after injection. On the basis of the data for these 4 patients (mean injected dose, 231 MBq), the radiation exposure of a (68)Ga-PSMA-617 PET/CT was identified.
Intense tracer uptake was observed in the kidneys and salivary glands. In 14 of 19 patients (73.7%), at least 1 lesion suspected of being a tumor was detected at 3 h after injection. Of 53 representative tumor lesions selected at 3 h after injection, 47 lesions were visible at 1 h after injection. The mean tumor-to-background ratio for maximum standardized uptake value was 20.4 ± 17.3 (range, 2.3-84.0) at 1 h after injection and 38.2 ± 38.6 (range, 3.6-154.3) at 3 h after injection. The average radiation exposure (effective dose) was approximately 0.021 mSv/MBq.
Within healthy organs, the kidneys and salivary glands showed the highest (68)Ga-PSMA-617 uptake. The radiation exposure was relatively low. (68)Ga-PSMA-617 shows PCa lesions with high contrast. Images obtained between 2 and 3 h after injection seem to be the best option with regard to radiotracer uptake and tumor contrast. Later images can help to clarify unclear lesions.
PSMA has shown to be a promising target for diagnosis and therapy (theranostics) of prostate cancer. We have reviewed developments in the field of radio- and fluorescence-guided surgery and targeted ...photodynamic therapy as well as multitargeting PSMA inhibitors also addressing albumin, GRPr and integrin α
β
. An overview of the regulatory status of PSMA-targeting radiopharmaceuticals in the USA and Europe is also provided. Technical and quality aspects of PSMA-targeting radiopharmaceuticals are described and new emerging radiolabeling strategies are discussed. Furthermore, insights are given into the production, application and potential of alternatives beyond the commonly used radionuclides for radiolabeling PSMA inhibitors. An additional refinement of radiopharmaceuticals is required in order to further improve dose-limiting factors, such as nephrotoxicity and salivary gland uptake during endoradiotherapy. The improvement of patient treatment achieved by the advantageous combination of radionuclide therapy with alternative therapies is also a special focus of this review.
Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently ...developed the fluorine-18-labelled PSMA-ligand
FPSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after
FDCFPyL and
FDCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of
FPSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the
FPSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand
FPSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known
FFDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.
Biochemical recurrence (BCR) is a concern for prostate cancer patients after local treatment.
Ga-labeled prostate-specific membrane antigen (PSMA) ligands have significantly improved prostate cancer ...imaging. However, several
F-labeled ligands that were developed as fluorinated tracers might present advantages. In this study, we analyzed the potential of
F-PSMA-1007 in patients with BCR.
Twelve patients with BCR after local treatment underwent PET/CT scans 1 and 3 h after injection of
F-PSMA-1007.
F-PSMA-1007 PET/CT detected lesions in 9 of 12 patients (75%). A significant difference was observed when comparing the tracer uptake in
F-PSMA-1007-positive lesions 1 and 3 h after injection (median SUV
, 7.00 vs. 11.34;
< 0.001;
= 76). Forty-four (88%) of 50
F-PSMA-1007-positive lymph nodes had a short-axis diameter of less than 8 mm.
In this pilot study,
F-PSMA-1007 PET/CT presented high potential for localization of recurrent disease in prostate cancer patients with BCR.
Introduction: Ga‐68 DOTATATE (Ga‐octreotate, GaTate) positron emission tomography (PET)/CT has multiple advantages compared with conventional and In‐111 octreotide imaging for neuroendocrine tumours ...and other somatostatin‐receptor expressing tumours. This study assesses the management impact of incremental diagnostic information obtained from this technique compared with conventional staging.
Methods: Fifty‐nine GaTate PET/CT studies were performed over an 18‐month period (52 proven or suspected gastro‐entero‐pancreatic or bronchial neuroendocrine tumours and seven neural crest/mesenchymal tumours). A retrospective blinded review was performed on the number of abnormalities (1, 2–5 or >5) within defined regions with comparison to conventional imaging to assess incremental diagnostic information. Subsequent management impact (high, moderate or low) was determined by clinical review and follow up to assess pre‐PET stage, treatment intent and post‐PET management change.
Results: Eighty‐eight percent of GaTate studies were abnormal. Compared with conventional and In‐111 octreotide imaging, additional information was provided by GaTate PET/CT in 68 and 83% of patients, respectively. Management impact was high (inter‐modality change) in 47%, moderate (intra‐modality change) in 10% and low in 41% (not assessable in 2%). High management impact included directing patients to curative surgery by identifying a primary site and directing patients with multiple metastases to systemic therapy.
Conclusion: GaTate PET/CT imaging provides additional diagnostic information in a high proportion of patients with consequent high management impact. GaTate PET/CT could replace 1In‐111 octreotide scintigraphy at centres where it is available given its superior accuracy, faster acquisition and lower radiation exposure. Rapid implementation could be achieved by allowing substitutional funding in the Medicare Benefit Schedule.
To summarize the research activities of the "clinical research group heavy ion therapy", funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics ...(grading, hypoxia) on local tumor control after carbon (
C-) ion- and photon irradiations.
Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either
C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days. The relative biological effectiveness (RBE) of
C-ions was calculated from TCD
-values (dose at 50% tumor control probability) of photons and
C-ions and correlated with intrinsic tumor parameters. For the HI-subline, larger tumors (diameter 18 mm) were irradiated with either carbon ions, oxygen ions or photons under ambient as well as hypoxic conditions to determine the variability of the RBE under different oxygenation levels. In addition, imaging, histology and molecular analyses were performed to decipher the underlying mechanisms.
Experimental results revealed (i) a smaller variation of the TCD
-values between the three tumor sublines for
C-ions (23.6 - 32.9 Gy) than for photons (38.2 - 75.7 Gy), (ii) steeper dose-response curves for
C-ions, and (iii) an RBE that increased with tumor grading (1.62 ± 0.11 (H) vs 2.08 ± 0.13 (HI) vs 2.30 ± 0.08 (AT1)). Large HI-tumors resulted in a marked increase of TCD
, which was increased further by 15% under hypoxic relative to oxic conditions. Noninvasive imaging, histology and molecular analyses identified hypoxia as an important radioresistance factor in photon therapy.
The dose-response studies revealed a higher efficacy of
C-ions relative to photon therapy in the investigated syngeneic tumor model. Hypoxia turned out to be at least one important radioresistance factor, which can be partly overridden by high-LET ion beams. This might be used to increase treatment effectiveness also in patients. The results of this project served as a starting point for several ongoing research projects.
PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to ...evaluate the change in the whole-body distribution of
F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used.
Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) (
= 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/μmol;
= 6), a medium-MA group (100.7 ± 23.1 GBq/μmol;
= 6), and a low-MA group (10.80 ± 2.84 GBq/μmol;
= 6). Static PET scans were performed 1 h after injection (scan duration, 10 min). SUV
in tumor and normal organs was compared by the multiple-comparison test. Immunohistochemical staining and Western blot analysis were performed to confirm expression of PSMA in tumor, salivary gland, and kidney.
The low-MA group (SUV
, 1.12 ± 0.30) showed significantly lower uptake of
F-PSMA-1007 in tumor than did the high-MA group (1.97 ± 0.77) and the medium-MA group (1.81 ± 0.57). On the other hand, in salivary gland, both the low-MA group (SUV
, 0.24 ± 0.04) and the medium-MA group (0.57 ± 0.08) showed significantly lower uptake than the high MA group (1.27 ± 0.28). The tumor-to-salivary gland SUV
ratio was 1.73 ± 0.55 in the high-MA group, 3.16 ± 0.86 in the medium-MA group, and 4.78 ± 1.29 in the low-MA group. The immunohistochemical staining and Western blot analysis revealed significant overexpression of PSMA in tumor and low expression in salivary gland and kidney.
A decrease in the MA level of the injected
F-PSMA-1007 solution resulted in decreased uptake in tumor and, to a greater degree, in normal salivary gland. Thus, there is a possibility of minimizing the adverse effects in salivary gland by setting an appropriate MA level in PSMA-targeting therapy.
PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to ...evaluate the change in the whole-body distribution of 18F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used. Methods: Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) (n = 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/μmol; n = 6), a medium-MA group (100.7 ± 23.1 GBq/μmol; n = 6), and a low-MA group (10.80 ± 2.84 GBq/μmol; n = 6). Static PET scans were performed 1 h after injection (scan duration, 10 min). SUVmean in tumor and normal organs was compared by the multiple-comparison test. Immunohistochemical staining and Western blot analysis were performed to confirm expression of PSMA in tumor, salivary gland, and kidney. Results: The low-MA group (SUVmean, 1.12 ± 0.30) showed significantly lower uptake of 18F-PSMA-1007 in tumor than did the high-MA group (1.97 ± 0.77) and the medium-MA group (1.81 ± 0.57). On the other hand, in salivary gland, both the low-MA group (SUVmean, 0.24 ± 0.04) and the medium-MA group (0.57 ± 0.08) showed significantly lower uptake than the high MA group (1.27 ± 0.28). The tumor-to-salivary gland SUVmean ratio was 1.73 ± 0.55 in the high-MA group, 3.16 ± 0.86 in the medium-MA group, and 4.78 ± 1.29 in the low-MA group. The immunohistochemical staining and Western blot analysis revealed significant overexpression of PSMA in tumor and low expression in salivary gland and kidney. Conclusion: A decrease in the MA level of the injected 18F-PSMA-1007 solution resulted in decreased uptake in tumor and, to a greater degree, in normal salivary gland. Thus, there is a possibility of minimizing the adverse effects in salivary gland by setting an appropriate MA level in PSMA-targeting therapy.
Background
18
FPSMA-1007, a positron emission tomography (PET) tracer, specifically targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer. PSMA-PET is ...effective especially for regional detection of biochemical recurrence, which significantly affects patient management. Herein, we established and optimized a one-step radiolabeling protocol to separate and purify
18
FPSMA-1007 with a CFN-MPS200 synthesizer for clinical application.
Results
A dedicated single use cassette and synthesis program for
18
FPSMA-1007 was generated using a single-step method for direct precursor radiolabeling. In the cassette, three tube types (fluoro-elastomer, PharMed® BPT, silicone) and two different precursor salts (trifluoroacetic acid or acetic acid) were compared for optimization. Furthermore, three-lot tests were performed under optimized conditions for quality confirmation. Activity yields and mean radiochemical purity of
18
FPSMA-1007 were > 5000 MBq and 95%, respectively, at the end of synthesis, and the decay-corrected mean radiochemical yield from all three cassettes was approximately 40% using a trifluoroacetic acid salt precursor. Fluoro-elastomer tubings significantly increased the amount of non-radioactive PSMA-1007 (8.5 ± 3.1 μg/mL) compared to those with other tubings (0.3 μg/mL). This reduced the molar activity of
18
FPSMA-1007 synthesized in the cassette assembled by fluoro-elastomer tubings (46 GBq/μmol) compared to that with PharMed® BPT and silicone tubings (1184 and 1411 GBq/μmol, respectively). Residual tetrabutylammonium, acetonitrile, and dimethyl sulfoxide levels were < 2.6 μg/mL, < 8 ppm, and < 11 ppm, respectively, and ethanol content was 8.0–8.1% in all three cassettes and two different salts. Higher activity yields, radiochemical purities, and decay-corrected radiochemical yields were obtained using an acetic acid salt precursor rather than a trifluoroacetic acid salt precursor (7906 ± 1216 MBq, 97% ± 0%, and 56% ± 4%). In the three-lot tests under conditions optimized with silicone cassettes and acetic acid salt precursor, all quality items passed the specifications required for human use.
Conclusions
We successfully automated the production of
18
FPSMA-1007 for clinical use and optimized synthesis procedures with a CFN-MPS200 synthesizer using a silicone cassette and acetic acid salt precursor. Cassette availability will facilitate a wide spread use of
18
FPSMA-1007-PET, leading to an effective prostate cancer management.
The aim of this study was to evaluate the novel probe (18)F-6-fluoro-N-2-(diethylamino)ethyl pyridine-3-carboxamide ((18)F-MEL050) for the imaging of primary and metastatic melanoma.
PET using ...(18)F-MEL050 was performed in murine models of melanoma. The specificity of (18)F-MEL050 was studied by comparing its accumulation in pigmented B16-F0 allograft tumors with that of human amelanotic A375 xenografts using PET and high-resolution autoradiography. (18)F-MEL050 PET results were compared with (18)F-FDG PET, the current standard in melanoma molecular imaging. To test the ability of (18)F-MEL050 to assess the metastatic spread of melanoma, a murine model of lung metastasis was imaged by PET/CT, and results correlated with physical assessment of tumor burden in the lungs.
In pigmented B16-F0 grafts, (18)F-MEL050 PET yielded a tumor-to-background ratio of approximately 20:1 at 1 h and greater than 50:1 at 2 and 3 h. In the B16-F0 melanoma allograft model, tumor-to-background ratio was more than 9-fold higher for (18)F-MEL050 than for (18)F-FDG (50.9 +/- 6.9 vs. 5.8 +/- 0.5). No uptake was observed in the amelanotic melanoma xenografts. Intense uptake of (18)F-MEL050 was evident in metastatic lesions in the lungs of B16-BL6 tumor-bearing mice on PET at 2 h after tracer injection, with high concordance between (18)F-MEL050 accumulation on PET/CT and tumor burden determined at necroscopy.
(18)F-MEL050 has a rapid tumor uptake and high retention with specificity for melanin, suggesting great potential for noninvasive clinical evaluation of suspected metastatic melanoma.
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