Dataset Information

Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

ABSTRACT:

Aim

To investigate whether modifications of prostate-specific membrane antigen (PSMA)-targeted radiolabeled urea-based inhibitors could reduce salivary gland uptake and thus improve tumor-to-salivary gland ratios, several analogs of a high affinity PSMA ligand were synthesized and evaluated in in vitro and in vivo studies.

Methods

Binding motifs were synthesized 'on-resin' or, when not practicable, in solution. Peptide chain elongations were performed according to optimized standard protocols via solid-phase peptide synthesis. In vitro experiments were performed using PSMA⁺ LNCaP cells. In vivo studies as well as ?SPECT/CT scans were conducted with male LNCaP tumor xenograft-bearing CB17-SCID mice.

Results

PSMA ligands with A) modifications within the central Zn²⁺-binding unit, B) proinhibitor motifs and C) substituents & bioisosteres of the P1'-?-carboxylic acid were synthesized and evaluated. Modifications within the central Zn²⁺-binding unit of PSMA-10 (Glu-urea-Glu) provided three compounds. Thereof, only ^natLu-carbamate I (^natLu-3) exhibited high affinity (IC₅₀?=?7.1?±?0.7?nM), but low tumor uptake (5.31?±?0.94% ID/g, 1?h p.i. and 1.20?±?0.55% ID/g, 24?h p.i.). All proinhibitor motif-based ligands (three in total) exhibited low binding affinities (>?1??M), no notable internalization and very low tumor uptake (natLu-11 revealed high affinity (IC₅₀?=?16.4?±?3.8?nM), but also this inhibitor showed low tumor uptake (3.40?±?0.63% ID/g, 1?h p.i. and 0.68?±?0.16% ID/g, 24?h p.i.). Salivary gland uptake in mice remained at an equally low level for all compounds (between 0.02?±?0.00% ID/g and 0.09?±?0.03% ID/g), wherefore apparent tumor-to-submandibular gland and tumor-to-parotid gland ratios for the modified peptides were distinctly lower (factor 8-45) than for [¹⁷⁷Lu]Lu-PSMA-10 at 24?h p.i.

Conclusions

The investigated compounds could not compete with the in vivo characteristics of the EuE-based PSMA inhibitor [¹⁷⁷Lu]Lu-PSMA-10. Although two derivatives (3 and 11) were found to exhibit high affinities towards LNCaP cells, tumor uptake at 24?h p.i. was considerably low, while uptake in salivary glands remained unaffected. Optimization of the established animal model should be envisaged to enable a clear identification of PSMA-targeting radioligands with improved tumor-to-salivary gland ratios in future studies.

SUBMITTER: Felber VB

PROVIDER: S-EPMC7910394 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

Felber Veronika Barbara VB Valentin Manuel Amando MA Wester Hans-Jürgen HJ

EJNMMI radiopharmacy and chemistry 20210226 1

<h4>Aim</h4>To investigate whether modifications of prostate-specific membrane antigen (PSMA)-targeted radiolabeled urea-based inhibitors could reduce salivary gland uptake and thus improve tumor-to-salivary gland ratios, several analogs of a high affinity PSMA ligand were synthesized and evaluated in in vitro and in vivo studies.<h4>Methods</h4>Binding motifs were synthesized 'on-resin' or, when not practicable, in solution. Peptide chain elongations were performed according to optimized standa ...[more]

PMID: 33638060

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Project description:RationalePSMA-directed therapy for metastatic prostate cancer is gaining adoption as a treatment option. However, accumulation of 177Lu/225Ac-PSMA in the salivary glands remains a problem, with risk of dose-limiting xerostomia and potentially severe effect on the quality of life. Gustatory stimulation is an approach that has commonly been used in radioactive iodine therapy to reduce accumulation in the salivary glands. However, based on theoretical differences in biodistribution, it was hypothesized that this could potentially lead to adverse increased toxicity for PSMA-ligand therapy. The primary objective of this work was to determine if gustatory stimulation by eating an assortment of sweet/fatty/acidic foods during the biodistribution phase of [18F]DCFPyl could result in a clinically relevant (> 30%) change in the uptake of the tracer in the salivary glands.Methods10 patients who already received a whole-body [18F]DCFPyl PET/CT scan for evaluation of prostate cancer, underwent a repeat (intervention) PET/CT scan within a month of the first (control) scan. During the intervention scan, patients chose from an assortment of sweet/fatty/acidic foods, which they then chewed and swallowed for a period of time starting 1 min before tracer administration to 10 min thereafter. Data from both scans were analyzed by placing VOIs on the major salivary glands and segmenting them using relative thresholds.ResultsA slight increase in PSMA uptake in the parotid glands was observed on the intervention scan when compared to the baseline scan (+ 7.1% SULmean and + 9.2% SULmax, p < 0.05). No significant difference in PSMA uptake in the submandibular glands was seen.ConclusionsEating only slightly increases uptake of [18F]DCFPyl in the parotid glands. We nonetheless recommend refraining from gustatory stimulation during the administration and early biodistribution phase of radionuclide therapy with PSMA-ligands to reduce the risk of avoidable additional toxicity.

Project description:AimElevated kidney uptake in insulinoma patients remains a major limitation of radiometallated exendin-derived ligands of the glucagon-like peptide 1 receptor (GLP-1R). Based on the previously published potent GLP-1R-activating undecapeptide 1, short-chained GLP-1R ligands were developed to investigate whether kidney uptake can be reduced by means of direct 18F-labeling (nuclide-based accelerated renal excretion) or the reduction of the overall ligand charge (ligand-based reduced kidney uptake).Materials & methodsGLP-1R ligands were prepared according to optimized standard protocols via solid-phase peptide synthesis (SPPS) or, when not practicable, via fragment coupling in solution. Synthesis of (2'-Et, 4'-OMe)4, 4'-L-biphenylalanine ((2'-Et, 4'-OMe)BIP), required for the preparation of 1, was accomplished by Suzuki-Miyaura cross-coupling. In vitro experiments were performed using stably transfected GLP-1R+ HEK293-hGLP-1R cells.ResultsIn contrast to the three reference ligands glucagon-like peptide 1 (GLP-1, IC50 = 23.2 ± 12.2 nM), [Nle14, Tyr(3-I)40]exendin-4 (IC50 = 7.63 ± 2.78 nM) and [Nle14, Tyr40]exendin-4 (IC50 = 9.87 ± 1.82 nM), the investigated GLP-1R-targeting small peptides (9-15 amino acids), including lead peptide 1, exhibited only medium to low affinities (IC50 > 189 nM). Only SiFA-tagged undecapeptide 5 (IC50 = 189 ± 35 nM) revealed a higher affinity than 1 (IC50 = 669 ± 242 nM).ConclusionThe investigated small peptides, including lead peptide 1, could not compete with favorable in vitro characteristics of glucagon-like peptide 1 (GLP-1), [Nle14, Tyr(3-I)40]exendin-4 and [Nle14, Tyr40]exendin-4. The auspicious EC50 values of 1 provided by the literature could not be transferred to competitive binding experiments. Therefore, the use of 1 as a basic scaffold for the design of further GLP-1R-targeting radioligands cannot be recommended. Further investigations might include the scaffold of 5, although substantial optimizations concerning affinity and lipophilicity would be required. In sum, GLP-1R-targeting radioligands with reduced kidney uptake could not be obtained in this work, which emphasizes the need for further ligands addressing this particular issue.

Dataset Information

Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

Aim

Methods

Results

Conclusions

Publications

Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

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