A Generator-Produced Gallium-68 Radiopharmaceutical for PET Imaging of Myocardial Perfusion

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Abstract

Lipophilic cationic technetium-99m-complexes are widely used for myocardial perfusion imaging (MPI). However, inherent uncertainties in the supply chain of molybdenum-99, the parent isotope required for manufacturing ⁹⁹Mo/ ^99mTc generators, intensifies the need for discovery of novel MPI agents incorporating alternative radionuclides. Recently, germanium/gallium (Ge/Ga) generators capable of producing high quality ⁶⁸Ga, an isotope with excellent emission characteristics for clinical PET imaging, have emerged. Herein, we report a novel ⁶⁸Ga-complex identified through mechanism-based cell screening that holds promise as a generator-produced radiopharmaceutical for PET MPI.

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Most cited references 36

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Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.

A.H. Schinkel, J.J.M. Smit, O van Tellingen … (1994)

We have generated mice homozygous for a disruption of the mdr1a (also called mdr3) gene, encoding a drug-transporting P-glycoprotein. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectin (100-fold) and to the carcinostatic drug vinblastine (3-fold). By comparison of mdr1a (+/+) and (-/-) mice, we found that the mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many tissues (especially in brain) and in decreased drug elimination. Our findings explain some of the side effects in patients treated with a combination of carcinostatics and P-glycoprotein inhibitors and indicate that these inhibitors might be useful in selectively enhancing the access of a range of drugs to the brain.

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P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model.

David Holtzman, David Prior, Abhay Sagare … (2005)

Accumulation of amyloid-beta (Abeta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Abeta production, suggesting that decreased elimination from the brain may contribute to elevated levels of Abeta and plaque formation. Efflux transport of Abeta across the blood-brain barrier (BBB) contributes to Abeta removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [I]Abeta40 and [I]Abeta42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Abeta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Abeta and enhanced Abeta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.

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Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence.

J F Kronauge, M. Isabel Chiu, D Piwnica-Worms (1990)

The fundamental myocellular uptake and retention mechanisms of hexakis (2-methoxyisobutyl isonitrile) technetium(I) (Tc-MIBI), a technetium-99m-based myocardial perfusion imaging agent, are unresolved. Because of the lipophilic cationic nature of Tc-MIBI, it may be distributed across biological membranes in response to transmembrane potential. To test this hypothesis, net uptake and retention of Tc-MIBI in cultured chick embryo ventricular myocytes were determined under conditions known to alter mitochondrial and plasma membrane potentials. Isovolumic depolarization of plasma membrane potentials in 130 mM extracellular K (Ko) 20 mM extracellular Cl buffer reduced net accumulation of Tc-MIBI from 171 +/- 16 (control) to 29 +/- 3.3 fmol intracellular Tc-MIBI/mg protein.nM extracellular Tc-MIBI. Unidirectional influx of Tc-MIBI in cells depolarized in 30 mM Ko buffer was also reduced; a resting plasma membrane potential of -87 +/- 6 mV was calculated from the Goldman flux equation using normal Ko/high Ko Tc-MIBI influx ratios. Addition of the potassium ionophore valinomycin to cells incubated in 130 mM Ko buffer to additionally depolarize mitochondrial membrane potentials further reduced net uptake of Tc-MIBI to levels comparable to that found in nonviable freeze-thawed preparations ([Tc-MIBI]i/[Tc-MIBI]o = 1). By depolarizing mitochondrial (and in part plasma membrane) potentials with the protonophores 2,4-dinitrophenol and carbonyl cyanide m-chlorophenylhydrazone (CCCP) Tc-MIBI was rapidly depleted from 181 +/- 16 (control) to 16 +/- 2.6 and 31 +/- 4.2 fmol/mg protein.nMo, respectively, with kinetics that did not correlate with loss of cellular ATP content. CCCP alone inhibited 90 +/- 3% of net accumulation or 66 +/- 3% of unidirectional influx of Tc-MIBI in a concentration-dependent manner. By hyperpolarizing mitochondrial membrane potentials with the K+/H+ ionophore nigericin or the ATP synthase inhibitor oligomycin, net uptake and retention of Tc-MIBI were increased by 60 +/- 9% and 375 +/- 20%, respectively. Caffeine, as well as the respiratory chain electron transport inhibitor rotenone, did not significantly alter net cell uptake (p greater than 0.2). These data indicate that the fundamental myocellular uptake mechanism of Tc-MIBI involves passive distribution across plasma and mitochondrial membranes and that at equilibrium Tc-MIBI is sequestered within mitochondria by the large negative transmembrane potentials.

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Author and article information

Contributors

Ramasamy Paulmurugan: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 29 October 2014

Volume: 9

Issue: 10

Electronic Location Identifier: e109361

Affiliations

[1 ]BRIGHT Institute, Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America

[2 ]Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri, United States of America

[3 ]Departments of Cell Biology and Physiology and Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America

[4 ]Department of Chemistry and Biochemistry, University of Missouri, St. Louis, Missouri, United States of America

Stanford University School of Medicine, United States of America

Author notes

* E-mail: sharmav@ 123456mir.wustl.edu (VS); dpiwnica-worms@ 123456mdanderson.org (DPW)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: VS. Performed the experiments: JS SEH JLP HG NPR. Analyzed the data: VS DPW. Contributed to the writing of the manuscript: VS DPW.

Article

Publisher ID: PONE-D-14-19249

DOI: 10.1371/journal.pone.0109361

PMC ID: 4212944

PubMed ID: 25353349

SO-VID: f90f640e-a55b-46e6-b630-7b08e92f80b9

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 29 April 2014

Date accepted : 31 August 2014

Page count

Pages: 10

Funding

This study was supported in part by National Institutes of Health (NIH) grants RO1 HL111163 (VS), R33 AG033328 (VS), P50 CA94056 (DPW), and the American Health Assistance Foundation A2007-383 (VS). The Small Animal Imaging Core of Washington University Medical School is gratefully acknowledged (P30 CA91842). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

A Generator-Produced Gallium-68 Radiopharmaceutical for PET Imaging of Myocardial Perfusion

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Electron Channelling Contrast Imaging (ECCI)

Most cited references 36

Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.

P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model.

Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence.

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