Radiofluorinated Derivatives of 2-(Phosphonomethyl)pentanedioic Acid as Inhibitors of Prostate Specific Membrane Antigen (PSMA) for the Imaging of Prostate Cancer

Graham, Keith; Lesche, Ralf; Gromov, Alexey; Böhnke, Niels; Schäfer, Martina; Hassfeld, Jorma; Dinkelborg, Ludger; Kettschau, Georg

doi:10.1021/jm300710j

Cited by 30 publications

(7 citation statements)

References 33 publications

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“…Depending on the properties of drug molecules one or more pathways are likely to dominate. Thus in order to elucidate the mechanism of 2-PMPA delivery via intranasal route to the CSF and brain, and to get quantitative the measurements in primate brain radiolabeled agents such as radiofluorinated 2-PMPA [ 73 ] may provide a more viable option. Future studies to evaluate such mechanisms are underway.…”

Section: Discussionmentioning

confidence: 99%

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration

Rais¹,

Wozniak²,

Wu³

et al. 2015

PLoS ONE

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Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support intranasal delivery of 2-PMPA to deliver therapeutic concentrations in the brain and may facilitate its clinical development.

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Section: Discussionmentioning

confidence: 99%

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration

Rais¹,

Wozniak²,

Wu³

et al. 2015

PLoS ONE

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“…A series of preclinical studies evaluated the role of radiolabeled small-molecule PSMA inhibiting ligands for imaging of human PCa using various radionuclides such as 11 C 32 , 18 F 33 , 123 I 34 , 99m Tc 34 - 36 , and 68 Ga 37 , 38 . The compounds used in these studies can be classified into three groups: (1) the urea-based compounds, (2) the glutamate phosphoramidates and (3) the 2-(phosphinylmethyl) pentanedioic acids 21 ( figure 1 ). Overall, the PSMA ligands tested in these preclinical studies showed high tumor uptake peaking at 0.5 - 1 h in mice with PSMA-expressing tumors.…”

Section: Introductionmentioning

confidence: 99%

PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status

Lütje¹,

Heskamp²,

Cornelissen³

et al. 2015

Theranostics

201

152

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Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided.

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“…Since the expression of PSMA in the prostate is nearly 100-fold higher than in other tissues and prostate cancer exhibits a tenfold higher expression than the healthy prostate, PSMA has become a conspicuous target for nuclear medicine diagnostics and therapy very recently. Since the 1990s several radiopharmaceuticals directed against PSMA were established [ 8 – 12 ]. Today several groups use PSMA-based PET for the diagnostics of PCa with excellent sensitivity based on a very high contrast [ 13 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy

et al. 2015

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BackgroundProstate-specific membrane antigen (PSMA) is a promising target for diagnostics and therapy of prostate carcinoma (PCa). Based on the hypothesis that PSMA expression can be modulated by variations in androgen deprivation therapy (ADT), we investigated the binding of a PSMA-directed radiopharmaceutical in vitro in order to get an insight of the interactions between altered premedication and PSMA expression before repetitive PSMA-directed PET/CT for therapy response and targeted therapy implementation.MethodsThe human castration-resistant PCa cell line VCaP (CRPC) was treated with either 1 nmol/L testosterone (T) over 20 passages yielding the androgen-sensitive cell line (revCRPC) or with 5 μmol/L abiraterone acetate (AA) generating the abiraterone-tolerant subtype CRPCAA. In these cell lines, T and AA were varied by either supply or withdrawal of T and AA. PSMA expression of the three cell culture models was detected by Western blot and immunohistochemical staining. For quantitative measurement of tracer uptake, 0.3 nmol/L 68Ga-labelled PSMA-HBED-CC peptide (100–300 kBq/ml) was added to different treated parallel cultures (n = 9 each). Time-dependent uptake per 106 cells of each culture was calculated and evaluated. PSMA mRNA expression was investigated by qPCR.ResultsPSMA expression increased dependently on intensified ADT in all three basic cell lines. 68Ga-PSMA-HBED-CC uptake almost doubled during 3 h in all cell lines (p < 0.01). Compared to the basic cells, pre-incubation with abiraterone for 48 h resulted in a significant increased uptake in CRPC (p < 0.001). In revCRPC, 48-h AA pre-incubation resulted in an eightfold higher uptake after 3 h (p < 0.001). Additional withdrawal of external testosterone increased the uptake up to tenfold (p < 0.01). The increase of PSMA expression upon ADT and AA treatments was confirmed by qPCR and Western blot data. Furthermore, in CRPCAA, 48-h AA withdrawal increased the uptake up to fivefold (p < 0.01).ConclusionsThe investigated three PCa cell culture subtypes represent a serial preclinical model of androgen deprivation therapy as a proxy for clinical situations with differing basal PSMA expression. The uptake of PSMA-binding tracers could be stimulated by therapeutic effective short-term variation in premedication in all stages of ADT response. These complex interactions have to be considered in the interpretation of diagnostic imaging using PSMA ligands as well as in the optimal timing of PSMA-based therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0145-8) contains supplementary material, which is available to authorized users.

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Radiofluorinated Derivatives of 2-(Phosphonomethyl)pentanedioic Acid as Inhibitors of Prostate Specific Membrane Antigen (PSMA) for the Imaging of Prostate Cancer

Cited by 30 publications

References 33 publications

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration

PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy

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