Peripheral ganglia in healthy rats as target structures for the evaluation of PSMA imaging agents

Abstract

Background The recent implementation of PET with prostate specific membrane antigen (PSMA)-specific radiotracers into the clinical practice has resulted in the significant improvement of accuracy in the detection of prostate carcinoma (PCa). PSMA-expression in ganglia has been regarded as an important pitfall in prostate carcinoma-PET diagnostics but has not found any practical use for diagnosis or therapy. Methods We explored this phenomenon and demonstrated the applicability of peripheral ganglia in healthy rats as surrogates for small PSMA positive lesions for the preclinical evaluation of diagnostic PCa PET probes. Healthy rats were measured with PET/CT using the tracers [ 18 F]DCFPyL, [Al 18 F]PSMA-11 and [ 68 Ga]PSMA-11. Sections of ganglia were stained with an anti-PSMA antibody. [ 18 F]DCFPyL uptake in ganglia was compared to that in LNCaP tumor xenografts in mice. Results Whereas [ 18 F]DCFPyL and [ 68 Ga]PSMA-11 were stable in vivo and accumulated in peripheral ganglia, [Al 18 F]PSMA-11 suffered from fast in vivo deflourination resulting in high bone uptake. Ganglionic PSMA expression was confirmed by immunohistochemistry. [ 18 F]DCFPyL uptake and signal-to-noise ratio in the superior cervical ganglion was not significantly different from LNCaP xenografts. Conclusions Our results demonstrated the non-inferiority of the novel model compared to conventionally used tumor xenografts in immune compromised rodents with regard to reproducibility and stability of the PSMA signal. Furthermore, the model involves less expense and efforts while it is permanently available and avoids tumor-growth associated animal morbidity and distress. To the best of our knowledge, this is the first tumor-free model suitable for the in vivo evaluation of tumor imaging agents.

High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

“…In a triple negative breast cancer xenograft, the localization of PSMA was detected in the xenograft-associated endothelial cells as well as on the tumor cells [7]. Also, benign tissue like the cervical ganglia possesses a very strong PSMA expression [8].…”

7-[18F]Fluoro-8-azaisatoic Anhydrides: Versatile Prosthetic Groups for the Preparation of PET Tracers

“…The PET probes (60.3 ± 5.6 MBq) were evaluated by μPET imaging in healthy rats, using the PSMA-expressing sympathetic and dorsal root ganglia as surrogates for small PSMA-positive lesions (for details, see refs , and Section 7 in the Supporting Information). This approach is particularly useful for the initial screening of new PSMA radioligands, as the lower inter- and intra-individual variance of tracer uptake compared to tumor models enables a more reliable comparison of multiple tracers. , All tracers accumulated in PSMA-expressing structures, and uptake was strongly reduced by co-injection of the PSMA-inhibitor 2-PMPA (23 mg/kg) (Figure ; for time-activity curves with 2-PMPA, see Section 7.2 in the Supporting Information). In comparison to the established tracer [ 18 F]­JK-PSMA-7, , [ 18 F]­JK-PSMA-15 showed a significantly higher signal-to-background ratio during the uptake period of 90–120 min p.i.…”

“…The PET probes (60.3 ± 5.6 MBq) were evaluated by μPET imaging in healthy rats, using the PSMA-expressing sympathetic and dorsal root ganglia as surrogates for small PSMA-positive lesions (for details, see refs ( 4 , 10 ) and Section 7 in the Supporting Information ). This approach is particularly useful for the initial screening of new PSMA radioligands, as the lower inter- and intra-individual variance of tracer uptake compared to tumor models enables a more reliable comparison of multiple tracers.…”

“…Unlike conventional imaging techniques such as computed tomography or magnetic resonance imaging, which primarily provide anatomical information, PET can be used for functional imaging on the cellular or molecular level . For example, PET imaging with 68 Ga-labeled probes targeting prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein that is highly overexpressed on malignant prostate cells, − has proven instrumental for the detection and staging of prostate cancer (PCa). ,,, However, 68 Ga-labeled PSMA radioligands are increasingly replaced by ligands labeled with fluorine-18 (like [ 18 F]­DCFPyL, [ 18 F]­JK-PSMA-7, 10 or [ 18 F]­PSMA-1007), which is the most frequently used radionuclide for PET imaging. Important advantages of fluorine-18 over gallium-68 include the accessibility of [ 18 F]­fluoride ([ 18 F]­F – ) in >100 GBq quantities via the 18 O­(p,n) 18 F nuclear reaction and a longer half-life ( t 1/2 = 110 vs 68 min), which enable large-scale, centralized production and distribution of 18 F-labeled radioligands. , In addition, due to the lower positron energy of fluorine-18 compared to gallium-68 ( E max = 0.63 vs 1.9 MeV), imaging with 18 F-labeled probes offers an improved spatial resolution.…”

High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

“…In a triple negative breast cancer xenograft the localization of PSMA was detected in the xenograft-associated endothelial cells as well as on the tumor cells [7]. Also benign tissue like the cervical ganglia possess a very strong PSMA expression [8].…”