Name: positron emission tomography using 64-copper as a tracer for the study of copper-related disorders
Uploaded: 2023-04-28T12:40:00
Description: Watch this Scientific Journal Video about Positron Emission Tomography Using 64-Copper as a Tracer for the Study of Copper-Related Disorders at JoVE.com

Supported by a grant from The Memorial Foundation of Manufacturer Vilhelm Pedersen &#38; Wife. The foundation played no role in the planning or any other phase of the study.

A few clinical trials using this 64Cu PET/CT or PET/MRI protocol have been approved by the Regional Ethics Committee of&#160;Region Midt, Denmark [1-10-72-196-16 (EudraCT 2016-001975-59), 1-10-72-41-19 (EudraCT 2019-000905-57), 1-10-72-343-20 (EudraCT 2020-005832-31), 1-10-72-25-21 (EudraCT 2021-000102-25), and 1-10-72-15-22 (EudraCT 2021-005464-21)]. Written informed consent was obtained from the participants at enrollment. The inclusion criteria for all participants were age &#62;18, and for females the use ...

<ol>
	<li>T&#252;mer, Z., M&#248;ller, L. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Menkes+disease.">Menkes disease.</a> European Journal of Human Genetics. 18 (5), 511-518 (2010).</li><li>Ala, A., Walker, A. P., Ashkan, K., Dooley, J. S., Schilsky, M. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wilson's+disease.">Wilson's disease.</a> The Lancet. 369 (9559), 397-408 (2007).</li><li>Owen, C. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Absorption+and+excretion+of+Cu64-labeled+copper+by+the+rat.">Absorption and excretion of Cu64-labeled copper by the rat.</a> The American Journal of Physiology-Legacy Content. 207 (6), 1203-1206 (1964).</li><li>Osborn, S. B., Roberts, C. N., Walshe, J. 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M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Studies+with+radioactive+copper+(64Cu+and+67Cu);+the+incorporation+of+radioactive+copper+into+caeruloplasmin+in+Wilson's+disease+and+in+primary+biliary+cirrhosis.">Studies with radioactive copper (64Cu and 67Cu); the incorporation of radioactive copper into caeruloplasmin in Wilson's disease and in primary biliary cirrhosis.</a> Clinical Science. 41 (3), 189-202 (1971).</li><li>Kume, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+semi-automated+system+for+the+routine+production+of+copper-64.">A semi-automated system for the routine production of copper-64.</a> Applied Radiation and Isotopes: Including Data, Instrumentation and Methods for Use in Agriculture, Industry and Medicine. 70 (8), 1803-1806 (2012).</li><li>Ohya, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Efficient+preparation+of+high-quality+64Cu+for+routine+use.">Efficient preparation of high-quality 64Cu for routine use.</a> Nuclear Medicine and Biology. 43 (11), 685-691 (2016).</li><li>Koole, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=EANM+guidelines+for+PET-CT+and+PET-MR+routine+quality+control.">EANM guidelines for PET-CT and PET-MR routine quality control.</a> Zeitschrift f&#252;r Medizinische Physik. , (2022).</li><li>Sandahl, T. 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The method is like any other PET method, but the long half-life of 12.7 h offers the opportunity to investigate long-term copper fluxes (we have good results from up to 68 h after IV tracer injection). All steps in the protocol must be handled by personnel familiar with PET, although they are no more critical than any other PET examination.
Troubleshooting 
Because we often use 64Cu for long-term investigations, the PET signal will be noisier than usual. This i...

Copper is a vital catalytic cofactor that drives multiple important biochemical processes essential for life, and defects in copper homeostasis are directly responsible for human diseases. Mutations in the ATP7A or ATP7B genes, encoding copper-transporting ATPases, cause Menke&#39;s and Wilson diseases, respectively. Menke&#39;s disease (ATP7A) is a rare lethal disorder of intestinal copper hyperaccumulation with severe copper deficiency in peripheral tissues and deficits in copper-dependent enzymes1. Wilson disease (WD) (ATP7B) is a rare disease characterized by the inability to excrete excess copper to bile, resulting in copper overload and subsequent organ damage, most severely affecting the liver and brain2.
Studies on copper metabolism have utilized radiolabeled copper (usually 64-copper [64Cu] or 67-copper) for decades, and these studies have proven invaluable for our understanding of mammalian copper metabolism, including absorption site and excretion pathways3,4,5,6. Previously, gamma counters were used to detect the radioactive signal with a limited anatomical resolution, but recently, 64Cu positron emission tomography (PET) combined with computed tomography (CT) or magnetic resonance imaging (MRI) has been introduced in both human and animal studies. Today, PET scanners have such a high sensitivity that it is possible to track 64Cu for up to 70 h after injection. The long half-life of 12.7 h for 64Cu allows for the long-term assessment of copper fluxes. This improvement in resolution has just recently entered the field of copper studies, and studies on normal and pathological copper metabolism, as well as studies evaluating the impact of specific treatments, are starting to emerge. Additionally, the introduction of whole-body PET scanners with an extended field-of-view will further enhance the sensitivity of these examinations.
This methodological paper aims to enable clinicians and scientists to add 64Cu PET CT/MRI to the existing repertoire of tools as a robust and easy-to-use method for assessing copper metabolism in a manner comparable between nuclear medicine departments. The production of 64Cu copper can be carried out using different methods and is usually performed at special facilities. Among the nuclear reactions, the 64Ni (p, n) 64Cu method is widely used, since a high production yield of 64Cu can be obtained with low energy protons in this route7,8. A detailed description of the production methods is out of the scope of this work, and availability will differ by country and region.
In this article, we first describe the preparation of the necessary radiochemistry and the tracer. Then, the principles for preparing the PET/CT or PET/MRI scanners are demonstrated.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>0.22 micrometer sterilizing filter</td>
			<td>Merck Life Science</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Cannula 21 G 50 mm</td>
			<td>BD Microlance</td>
			<td>301155</td>
			<td></td>
		</tr>
		<tr>
			<td>Cannula 25 G 16 mm</td>
			<td>BD Microlance</td>
			<td>300600</td>
			<td></td>
		</tr>
		<tr>
			<td>Dose calibrator</td>
			<td>Capintec CRC-PC calibrator</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>PET/CT scanner</td>
			<td>Siemens: Biograph</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>PET/MR scanner</td>
			<td>GE Signa</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>PMOD version 4.0</td>
			<td>PMOD Technologies LLC</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Saline solution 0.9% NaCl</td>
			<td>Fresenius Kabi</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium acetate trihydrate BioUltra</td>
			<td>Sigma Aldrich</td>
			<td>71188</td>
			<td></td>
		</tr>
		<tr>
			<td>Solid 64CuCl2</td>
			<td>Danish Technical University Ris&#248;</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Sterile water</td>
			<td>Fresenius Kabi</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Venflon 22 G 25 mm</td>
			<td>BD Venflon Pro Safety</td>
			<td>393280</td>
			<td></td>
		</tr>
	</tbody>
</table>

positron emission tomography using 64-copper as a tracer for the study of copper-related disorders

Copper is an essential trace element, functioning in catalysis and signaling in biological systems. Radiolabeled copper has been used for decades in studying basic human and animal copper metabolism and copper-related disorders, such as Wilson disease (WD) and Menke&#39;s disease. A recent addition to this toolkit is 64-copper (64Cu) positron emission tomography (PET), combining the accurate anatomical imaging of modern computed tomography (CT) or magnetic resonance imaging (MRI) scanners with the biodistribution of the 64Cu PET tracer signal. This allows the in vivo tracking of copper fluxes and kinetics, thereby directly visualizing human and animal copper organ traffic and metabolism. Consequently, 64Cu PET is well-suited for evaluating clinical and preclinical treatment effects and has already demonstrated the ability to diagnose WD accurately. Furthermore, 64Cu PET/CT studies have proven valuable in other scientific areas like cancer and stroke research. The present article shows how to perform 64Cu PET/CT or PET/MR in humans. Procedures for 64Cu handling, patient preparation, and scanner setup are demonstrated here.

Dose calculation 
Based on dosimetry calculations, the effective radioactivity dose for IV administration is 62 &#177; 5 &#181;Sv/MBq tracer10. Thus, a 50 MBq dose is recommended depending on the time frame. Up to 75-80 MBq is applicable for longer examinations and provides good-quality images without exceeding an ethically approved dose. The effective dose for oral administration is 113 &#177; 1 &#181;Sv/MBq tracer, due to intestinal accumulation of the tracer. Thus, a lower...

Watch this Scientific Journal Video about Positron Emission Tomography Using 64-Copper as a Tracer for the Study of Copper-Related Disorders at JoVE.com

Positron Emission Tomography Using 64-Copper as a Tracer for the Study of Copper-Related Disorders

The present protocol describes how to perform 64Cu PET/CT and PET/MRI imaging in humans to study copper-related disorders, such as Wilson disease, and the treatment effect on copper metabolism.

Copper is an essential trace element, functioning in catalysis and signaling in biological systems. Radiolabeled copper has been used for decades in ...

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