Dataset Information

In vivo characterization of [¹⁸F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.

ABSTRACT:

Purpose

Multidrug resistance (MDR) impedes cancer treatment. Two efflux transporters from the ATP-binding cassette (ABC) family, ABCB1 and ABCG2, may contribute to MDR by restricting the entry of therapeutic drugs into tumor cells. Although a higher expression of these transporters has been correlated with an unfavorable response to chemotherapy, transporter expression does not necessarily correlate with function. In this study, we characterized the pharmacological properties of [¹⁸F]AVT-011, a new PET radiotracer for imaging transporter-mediated MDR in tumors.

Methods

AVT-011 was radiolabeled with ¹⁸F and evaluated with PET imaging in preclinical models. Transport of [¹⁸F]AVT-011 by ABCB1 and/or ABCG2 was assessed by measuring its uptake in the brains of wild-type, Abcb1a/b^-/-, and Abcg2^-/- mice at baseline and after administration of the ABCB1 inhibitor tariquidar (n = 5/group). Metabolism and biodistribution of [¹⁸F]AVT-011 were also measured. To measure ABCB1 function in tumors, we performed PET experiments using both [¹⁸F]AVT-011 and [¹⁸F]FDG in mice bearing orthotopic breast tumors (n = 7-10/group) expressing clinically relevant levels of ABCB1.

Results

At baseline, brain uptake was highest in Abcb1a/b^-/- mice. After tariquidar administration, brain uptake increased 3-fold and 8-fold in wild-type and Abcg2^-/- mice, respectively, but did not increase further in Abcb1a/b^-/- mice. At 30 min after injection, the radiotracer was > 90% in its parent form and had highest uptake in organs of the hepatobiliary system. Compared with that in drug-sensitive tumors, uptake of [¹⁸F]AVT-011 was 32% lower in doxorubicin-resistant tumors with highest ABCB1 expression and increased by 40% with tariquidar administration. Tumor uptake of [¹⁸F]FDG did not significantly differ among groups.

Conclusion

[¹⁸F]AVT-011 is a dual ABCB1/ABCG2 substrate radiotracer that can quantify transporter function at the blood-brain barrier and in ABCB1-expressing tumors, making it potentially suitable for clinical imaging of ABCB1-mediated MDR in tumors.

SUBMITTER: Kannan P

PROVIDER: S-EPMC7299908 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

In vivo characterization of [<sup>18</sup>F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.

Kannan Pavitra P Füredi András A Dizdarevic Sabina S Wanek Thomas T Mairinger Severin S Collins Jeffrey J Falls Theresa T van Dam R Michael RM Maheshwari Divya D Lee Jason T JT Szakács Gergely G Langer Oliver O

European journal of nuclear medicine and molecular imaging 20191115 8

<h4>Purpose</h4>Multidrug resistance (MDR) impedes cancer treatment. Two efflux transporters from the ATP-binding cassette (ABC) family, ABCB1 and ABCG2, may contribute to MDR by restricting the entry of therapeutic drugs into tumor cells. Although a higher expression of these transporters has been correlated with an unfavorable response to chemotherapy, transporter expression does not necessarily correlate with function. In this study, we characterized the pharmacological properties of [<sup>18 ...[more]

PMID: 31729540

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Project description:IntroductionPrimary aldosteronism accounts for 6-15% of hypertension cases, the single biggest contributor to global morbidity and mortality. Whilst ~50% of these patients have unilateral aldosterone-producing adenomas, only a minority of these have curative surgery as the current diagnosis of unilateral disease is poor. Carbon-11 radiolabelled metomidate ([11C]MTO) is a positron emission tomography (PET) radiotracer able to selectively identify CYP11B1/2 expressing adrenocortical lesions of the adrenal gland. However, the use of [11C]MTO is limited to PET centres equipped with on-site cyclotrons due to its short half-life of 20.4?min. Radiolabelling a fluorometomidate derivative with fluorine-18 (radioactive half life 109.8?min) in the para-aromatic position ([18F]FAMTO) has the potential to overcome this disadvantage and allow it to be transported to non-cyclotron-based imaging centres.MethodsTwo strategies for the one-step radio-synthesis of [18F]FAMTO were developed. [18F]FAMTO was obtained via radiofluorination via use of sulfonium salt (1) and boronic ester (2) precursors. [18F]FAMTO was evaluated in vitro by autoradiography of pig adrenal tissues and in vivo by determining its biodistribution in rodents. Rat plasma and urine were analysed to determine [18F]FAMTO metabolites.Results[18F]FAMTO is obtained from sulfonium salt (1) and boronic ester (2) precursors in 7% and 32% non-isolated radiochemical yield (RCY), respectively. Formulated [18F]FAMTO was obtained with >99% radiochemical and enantiomeric purity with a synthesis time of 140?min from the trapping of [18F]fluoride ion on an anion-exchange resin (QMA cartridge). In vitro autoradiography of [18F]FAMTO demonstrated exquisite specific binding in CYP11B-rich pig adrenal glands. In vivo [18F]FAMTO rapidly accumulates in adrenal glands. Liver uptake was about 34% of that in the adrenals and all other organs were <12% of the adrenal uptake at 60?min post-injection. Metabolite analysis showed 13% unchanged [18F]FAMTO in blood at 10?min post-administration and rapid urinary excretion. In vitro assays in human blood showed a free fraction of 37.5%.Conclusions[18F]FAMTO, a new 18F-labelled analogue of metomidate, was successfully synthesised. In vitro and in vivo characterization demonstrated high selectivity towards aldosterone-producing enzymes (CYP11B1 and CYP11B2), supporting the potential of this radiotracer for human investigation.

Dataset Information

In vivo characterization of [¹⁸F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.

Purpose

Methods

Results

Conclusion

Publications

In vivo characterization of [<sup>18</sup>F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

In vivo characterization of [18F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.

Purpose

Methods

Results

Conclusion

Publications

In vivo characterization of [<sup>18</sup>F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

In vivo characterization of [¹⁸F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.