Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates

Maung, Jack; Mallari, Jeremy P.; Girtsman, Teri; Wu, Lizhong; Rowley, Jennifer A.; Santiago, Nicholas M.; Brunelle, Alan; Berkman, Clifford E.

doi:10.1016/j.bmc.2004.06.031

Cited by 72 publications

(62 citation statements)

References 28 publications

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“…The here aimed linker region is designed to elucidate the structureactivity relationships and to mimic the proven additional biologic interactions of HBED-CC with the binding pocket. Thus, an ideal linker length (26), polarity (27), size, flexibility (28), presence of aromatic groups (26), or hydrophobic functionality distal to the glutamic acid moiety (29) represents an effective strategy to design highly potent PSMA inhibitor-based radiotracers.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

et al. 2015

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Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. Methods: The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversedphase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent 67/68 Ga and 177 Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. Results: The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [K i ] 5 2.34 ± 2.94 nM on LNCaP; K i 5 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-tobackground contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. Conclusion: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.

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Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

et al. 2015

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“…The quenched incubation mixture was quickly buffered by the addition of 25 µl k 2 HPO 4 (0.1 M), vortexed, and centrifuged (10 min at 7,000 g). An 85 µl aliquot of the resulting supernatant was subsequently quantified by HPLC as previously described (32,33). IC 50 values were calculated using kaleida Graph 3.6 (Synergy Software).…”

Section: Detection Of Prostate-specific Membrane Antigen On Huvecs Inmentioning

confidence: 99%

Detection of prostate-specific membrane antigen on HUVECs in response to breast tumor-conditioned medium

Liu

Jabbes

Nedrow³

et al. 2011

Int J Oncol

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Abstract. Prostate-specific membrane antigen (PSMA), a well-known biomarker of prostate cancer, has also been found to be highly expressed in the neovasculature of multiple non-prostatic solid tumors. As a consequence, it has the potential to become a biomarker for tumor-associated vasculature. Herein, we describe an in vitro model for assessing PSMA expression associated with tube formation by primary human umbilical vein endothelial cells (HUVECs) cultured in Matrigel and induced by tumor-conditioned medium (TCM) derived from human breast cancer cells (MDA-MB-231). In contrast to vascular endothelial growth factor (VEGF)-containing endothelial cell medium, TCM induced higher expression of PSMA in HUVECs. The vessel-like tubes were detected by imaging with fluorescent PSMA inhibitors. Consequently, this in vitro model is expected to enable subsequent studies aimed at determining the role of PSMA in angiogenesis and factors that induce it.

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“…18 The use of HPLC in monitoring PSMA activity is an alternative approach to the more conventional radioisotopic assay which requires ion-exchange chromatography to selectively elute enzymatically liberated, radiolabeled glutamate.…”

Section: Introductionmentioning

confidence: 99%

Substrate specificity of prostate-specific membrane antigen

Anderson

Santiago

et al. 2007

Bioorganic & Medicinal Chemistry

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A series of putative dipeptide substrates of prostate specific membrane antigen (PSMA) was prepared that explored α-and β/γ-linked acidic residues at the P1 position and various chromophores at the P2 position, while keeping the P1' residue constant as L-Glu. Four chromophores were examined, including 4-phenylazobenzoyl, 1-pyrenebutyrl, 9-anthracenylcarboxyl-γ-aminobutyrl, and 4-nitrophenylbutyryl. When evaluating these chromophores, it was found that a substrate containing 4-phenylazobenzoyl at the P2 position was consumed most efficiently. Substitution at the P1 position with acidic residues showed that only γ-linked L-Glu and D-Glu were recognized by the enzyme, with the former being more readily proteolyzed. Lastly, binding modes of endogenous substrates and our best synthetic substrate (4-phenylazobenzoyl-Glu-γ-Glu) were proposed by computational docking studies into an X-ray crystal structure of the PSMA extracellular domain.

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Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates

Cited by 72 publications

References 28 publications

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

Detection of prostate-specific membrane antigen on HUVECs in response to breast tumor-conditioned medium

Substrate specificity of prostate-specific membrane antigen

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