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Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an ¹¹C-labeled radiotracer in rodents.

ABSTRACT: Nine new compounds targeting the transient receptor potential vanilloid-4 (TRPV4) were synthesized and their biological activities toward TRPV4 were determined using freshly isolated mouse skin macrophages through live cell Ca²⁺ imaging assay. Three compounds 4b, 4c, and 4i exhibited higher percentages of in vitro activation of TRPV4 as 48.1%, 59.3% and 33.5%, which are comparable to 56.4% activation response of the reported TRPV4 agonist GSK1016790A (3). The compound 4i was chosen for ¹¹C-radiosynthesis using its phenol precursor 4g to reacted with [¹¹C]methyl iodide. The radiosynthesis was achieved with good radiochemical yield (16 ± 5%), high chemical and radiochemical purity (>95%), and high molar activity (16-21 GBq/μmol, decay corrected to the end of bombardment, EOB n ≥ 4). Furthermore, the initial ex vivo biodistribution study in rats showed that [¹¹C]4i had higher uptake in kidney, liver and small intestine compared to other tissues with rapid washout.

SUBMITTER: Qiu L

PROVIDER: S-EPMC8627648 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an <sup>11</sup>C-labeled radiotracer in rodents.

Qiu Lin L Du Lixia L Liang Qianwa Q Hu Hongzhen H Tu Zhude Z

Bioorganic & medicinal chemistry letters 20200924 22

Nine new compounds targeting the transient receptor potential vanilloid-4 (TRPV4) were synthesized and their biological activities toward TRPV4 were determined using freshly isolated mouse skin macrophages through live cell Ca<sup>2+</sup> imaging assay. Three compounds 4b, 4c, and 4i exhibited higher percentages of in vitro activation of TRPV4 as 48.1%, 59.3% and 33.5%, which are comparable to 56.4% activation response of the reported TRPV4 agonist GSK1016790A (3). The compound 4i was chosen fo ...[more]

PMID: 32980513

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Project description:The prostate-specific membrane antigen (PSMA)-targeted radiohybrid (rh) ligand [177Lu]Lu-rhPSMA-7.3 has recently been assessed in a pretherapeutic dosimetry study on prostate cancer patients. In comparison to [177Lu]Lu-PSMA I&T, application of [177Lu]Lu-rhPSMA-7.3 resulted in a significantly improved tumor dose but also higher kidney accumulation. Although rhPSMA-7.3 has been initially selected as the lead compound for diagnostic application based on the characterization of its gallium complex, a systematic comparison of the most promising 177Lu-labeled rhPSMA ligands is still missing. Thus, this study aimed to identify the rhPSMA ligand with the most favorable pharmacokinetics for 177Lu-radioligand therapy. Methods: The 4 isomers of [177Lu]Lu-rhPSMA-7 (namely [177Lu]Lu-rhPSMA-7.1, -7.2, -7.3, and -7.4), along with the novel radiohybrid ligands [177Lu]Lu-rhPSMA-10.1 and -10.2, were compared with the state-of-the-art compounds [177Lu]Lu-PSMA I&T and [177Lu]Lu-PSMA-617. The comparative evaluation comprised affinity studies (half-maximal inhibitory concentration) and internalization experiments on LNCaP cells, as well as lipophilicity measurements. In addition, we determined the apparent molecular weight (AMW) of each tracer as a parameter for human serum albumin (HSA) binding. Biodistribution studies and small-animal SPECT imaging were performed on LNCaP-tumor bearing mice at 24 h after injection. Results: 177Lu labeling of the radiohybrids was performed according to the established procedures for the currently established PSMA-targeted ligands. All ligands showed potent binding to PSMA-expressing LNCaP cells, with affinities in the low nanomolar range and high internalization rates. Surprisingly, the most pronounced differences regarded the HSA-related AMW. Although [177Lu]Lu-rhPSMA-7 isomers demonstrated the highest AMW and thus strongest HSA interactions, [177Lu]Lu-rhPSMA-10.1 showed an AMW lower than for [177Lu]Lu-rhPSMA-7.3 but higher than for the 177Lu-labeled references PSMA I&T and PSMA-617. In biodistribution studies, [177Lu]Lu-rhPSMA-10.1 exhibited the lowest kidney uptake and fastest excretion from the blood pool of all rhPSMA ligands while preserving a high tumor accumulation. Conclusion: Clinical investigation of [177Lu]Lu-rhPSMA-10.1 is highly warranted to determine whether the favorable pharmacokinetics observed in mice will also result in high tumor uptake and decreased absorbed dose to kidneys and other nontarget tissues in patients.

Dataset Information

Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an ¹¹C-labeled radiotracer in rodents.

Publications

Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an <sup>11</sup>C-labeled radiotracer in rodents.

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Dataset Information

Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an 11C-labeled radiotracer in rodents.

Publications

Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an <sup>11</sup>C-labeled radiotracer in rodents.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an ¹¹C-labeled radiotracer in rodents.