Name: investigations on the ga(iii) complex of eob-dtpa and its 68ga radiolabeled analogue
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Description: Watch this Scientific Journal Video about Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue at JoVE.com

The authors have no acknowledgements.

1. Preparation of EOB-DTPA and Ga[EOB-DTPA]
Caution: Please consult all relevant material safety data sheets (MSDS) of the used organic solvents, acids and alkalines before use. Perform all steps in a fume hood and use personal protective equipment (safety glasses, gloves, lab coat).
<ol>
	<li>Isolation of EOB-DTPA from gadoxetic acid
	<ol>
		<li>Put 3 ml of 0.25 M gadoxetic acid injectable solution into a flask. Add 500 mg (5.6 mmol) of oxalic acid to the stirred solution.</li>
		<li>After stir...

<ol>
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EOB-DTPA is accessible through a multi-step synthesis33 but may just as well be isolated from available contrast agents containing gadoxetic acid. For this purpose, the central Gd(III) ion can be precipitated with an excess of oxalic acid. After removing Gd(III) oxalate and oxalic acid the ligand can be isolated by precipitation in cold water at pH 1.5. However, in order to enhance yields column chromatography of the filtrate can be performed instead or as a follow-up procedure. Either method yields the analyt...

Gadoxetic acid, a common name for the Gd(III) complex of the ligand EOB-DTPA1, is a frequently used contrast agent in hepatobiliary magnetic resonance imaging (MRI).2,3 Due to its specific uptake by liver hepatocytes and high percentage of hepatobiliary excretion it enables the localization of focal lesions and hepatic tumors.2-5 However, certain limitations of the MRI technique (e.g., toxicity of the contrast agents, limited applicability in patients with claustrophobia or metal implants) call for an alternative diagnostic tool.
Positron emission tomography (PET) is a molecular imaging method, wherein a small amount of a radioactive substance (tracer) is administered, upon which its distribution in the body is recorded by a PET scanner.6 PET is a dynamic method that allows for high spatial and temporal resolution of images as well as quantification of the results, without having to deal with the side-effects of MRI contrast agents. The informative value of the obtained metabolic information can be further increased by combination with anatomical data received from additional imaging methods, as most commonly achieved by hybrid imaging with computed tomography (CT) in PET/CT scanners.
The chemical structure of a tracer suitable for PET must include a radioactive isotope serving as positron emitter. Positrons have a short life-span since they almost immediately annihilate with electrons of the atom shells of surrounding tissue. By annihilation two 511 keV gamma photons with opposite direction of movement are emitted, which are recorded by the PET scanner.7,8 To form a tracer, PET nuclides may be bound covalently to a molecule, as is the case in 2-deoxy-2-[18F]fluoroglucose (FDG), the most extensively used PET tracer.7 However, a nuclide may also form coordinative bonds to one or several ligands (e.g., [68Ga]-DOTATOC9,10) or be applied as dissolved inorganic salts (e.g., [18F] sodium fluoride11). Altogether, the structure of the tracer is crucial as it determines its biodistribution, metabolism and excretion behavior.
A suitable PET nuclide should combine favorable characteristics like convenient positron energy and availability as well as a half-life adequate for the intended investigation. The 68Ga nuclide has become an essential force in the field of PET over the last two decades.12,13 This is mainly due to its availability through a generator system, which allows on-site labeling independently from the vicinity of a cyclotron. In a generator, the mother nuclide 68Ge is absorbed on a column from which the daughter nuclide 68Ga is eluted and subsequently labeled to a suitable chelator.6,14 Since the 68Ga nuclide exists as a trivalent cation just like Gd(III)10,13, chelating EOB-DTPA with 68Ga instead would yield a complex with the same overall negative charge as gadoxetic acid. Accordingly, that 68Ga tracer might combine a similar characteristic liver specificity with the suitability for PET imaging. Although gadoxetic acid is purchased and administered as disodium salt, in the following context we will refer to it as Gd[EOB-DTPA] and to the non-radioactive Ga(III) complex as Ga[EOB-DTPA], or 68Ga[EOB-DTPA] in case of the radiolabeled component for the sake of convenience.
To evaluate their applicability as tracers for PET, radioactive metal complexes need to be examined extensively in in vitro, in vivo or ex vivo experiments first. To determine the suitability for a respective medical problem, various tracer characteristics like biodistribution behavior and clearance profile, stability, organ specificity and cell or tissue uptake need to be investigated. Due to their non-invasive character, in vitro determinations are often performed prior to in vivo experiments. It is generally acknowledged that DTPA and its derivatives are of limited suitability as chelators for 68Ga due to these complexes lacking kinetic inertness, resulting in comparably fast decomposition when administered in vivo.14-20 This is primarily caused by apo-transferrin acting as a competitor for 68Ga in plasma. Nevertheless, we investigated this new tracer concerning its possible application in hepatobiliary imaging, wherein diagnostic information may be provided within minutes post-injection3,4,21-23, thereby not necessarily requiring long-term tracer stability. For this purpose we isolated EOB-DTPA from gadoxetic acid and initially performed the complexation with natural Ga(III), which exists as mixture of two stable isotopes, 69Ga and 71Ga. The complex thus obtained served as non-radioactive standard for the following chelation of 68Ga. We used established methods and simultaneously evaluated their suitability for determining the 68Galabeling efficiency of EOB-DTPA and to investigate the lipophilicity of the new 68Ga tracer and its stability in different media.

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		<tr height="21">
			<td height="21" style="height:21px;width:216px;">primovist</td>
			<td style="width:180px;">Bayer</td>
			<td style="width:119px;">-</td>
			<td style="width:167px;">0.25 M</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">gallium(III) chloride</td>
			<td style="width:180px;">Sigma-Aldrich Co.</td>
			<td style="width:119px;">450898</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">water (deionized)</td>
			<td style="width:180px;">-</td>
			<td style="width:119px;">-</td>
			<td>&#160;tap water deionizing equipment by Auma-Tec GmbH</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">hydrochloric acid 12 M</td>
			<td style="width:180px;">VWR</td>
			<td style="width:119px;">20252.29</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">sodium hydroxide</td>
			<td style="width:180px;">Polskie Odczynniki Chemiczne S.A.</td>
			<td style="width:119px;">810925429</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">oxalic acid</td>
			<td style="width:180px;">Sigma-Aldrich Co.</td>
			<td style="width:119px;">75688</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">ethyl acetate</td>
			<td style="width:180px;">Brenntag GmbH</td>
			<td style="width:119px;">10010447</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">silica gel</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.10832.9025</td>
			<td>Geduran Si 60 0,063-0,2 mm</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">TLC silica gel 60 F254</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.16834.0001</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">methanol</td>
			<td style="width:180px;">VWR</td>
			<td style="width:119px;">20903.55</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">ethanol</td>
			<td style="width:180px;">Brenntag GmbH</td>
			<td style="width:119px;">10018366</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">eiethylether</td>
			<td style="width:180px;">VWR</td>
			<td style="width:119px;">23807.468</td>
			<td>stored over KOH plates</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">ammonia solution (25 %)</td>
			<td style="width:180px;">VWR</td>
			<td style="width:119px;">1133.1</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">pH electrode</td>
			<td style="width:180px;">VWR</td>
			<td style="width:119px;">662-1657</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">stirring and heating unit</td>
			<td style="width:180px;">Heidolph</td>
			<td style="width:119px;">505-20000-00</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">pump</td>
			<td style="width:180px;">Ilmvac GmbH</td>
			<td style="width:119px;">322002</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">frit</td>
			<td style="width:180px;">-</td>
			<td style="width:119px;">custom design</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">NMR spectrometer</td>
			<td style="width:180px;">Bruker Coorporation</td>
			<td style="width:119px;">-</td>
			<td>Ultra Shield 400</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">mass spectrometer</td>
			<td style="width:180px;">Thermo Fisher Scientific Inc.</td>
			<td style="width:119px;">-</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">elemental analyser</td>
			<td>Hekatech GmbH Analysentechnik</td>
			<td style="width:119px;">-</td>
			<td>EuroVector EA 3000 CHNS</td>
		</tr>
		<tr height="25">
			<td height="25" style="height:25px;width:216px;">deuterated water D2O</td>
			<td style="width:180px;">euriso-top</td>
			<td style="width:119px;">D214</td>
			<td>99,90 % D</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Name</td>
			<td style="width:180px;">Company</td>
			<td style="width:119px;">Catalog Number</td>
			<td>Comments</td>
		</tr>
		<tr height="21">
			<td colspan="4" height="21" style="height:21px;width:681px;">Material/Equipment required for labeling procedures</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">68Ge/68Ga generator</td>
			<td style="width:180px;">ITG Isotope Technologies Garching GmbH</td>
			<td style="width:119px;">A150</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">pump and dispenser system</td>
			<td style="width:180px;">Scintomics GmbH</td>
			<td style="width:119px;">-</td>
			<td>Variosystem</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">hydrochloric acid 30 % (suprapur)</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.00318.1000</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">water (ultrapur)</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.01262.1000</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">sodium chloride (suprapur)</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.06406.0500</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">sodium acetate (suprapur)</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.06264.0050</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">glacial acetic acid (suprapur)</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.00066.0250</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">sodium citrate dihydrate</td>
			<td style="width:180px;">VEB Laborchemie Apolda</td>
			<td style="width:119px;">10782</td>
			<td>&#62;98.5%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">PS-H+ Cartridge (S)</td>
			<td style="width:180px;">Macherey-Nagel</td>
			<td style="width:119px;">731867</td>
			<td>Chromafix</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">apo-Transferrin</td>
			<td style="width:180px;">Sigma-Aldrich Co.</td>
			<td style="width:119px;">T2036</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">PBS&#160; buffer (tablets)</td>
			<td style="width:180px;">Sigma-Aldrich Co.</td>
			<td style="width:119px;">79382</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">human serum</td>
			<td style="width:180px;">Sigma-Aldrich Co.</td>
			<td style="width:119px;">H4522</td>
			<td>from human male AB plasma</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">flasks, columns etc.</td>
			<td style="width:180px;"></td>
			<td style="width:119px;">custom design</td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">pH electrode</td>
			<td style="width:180px;">Knick Elektronische Messger&#228;te GmbH &#38; Co. KG</td>
			<td style="width:119px;">765-Set</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">binary pump (HPLC)</td>
			<td style="width:180px;">Hewlett-Packard</td>
			<td style="width:119px;">G1312A (HP 1100)</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">UV Vis detector (HPLC)</td>
			<td style="width:180px;">Hewlett-Packard</td>
			<td style="width:119px;">G1315A (HP 1100)</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">radioactive detector (HPLC)</td>
			<td style="width:180px;">EGRC Berthold</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">HPLC C-18-PFP column</td>
			<td style="width:180px;">Advanced Chromatography Technologies Ltd.</td>
			<td style="width:119px;">ACE-1110-1503/A100528</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">HPLC glass vials</td>
			<td style="width:180px;">GTG Glastechnik Graefenroda GmbH</td>
			<td style="width:119px;">8004-HP-H/i3&#181;</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">pipette</td>
			<td style="width:180px;">Eppendorf</td>
			<td style="width:119px;">-</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">plastic vials</td>
			<td style="width:180px;">Sarstedt AG &#38; Co.</td>
			<td style="width:119px;">6542.007</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">plastic vials</td>
			<td style="width:180px;">Greiner Bio-One International GmbH</td>
			<td style="width:119px;">717201</td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">activimeter</td>
			<td style="width:180px;">MED Nuklear-Medizintechnik Dresden GmbH</td>
			<td style="width:119px;">-</td>
			<td>Isomed 2010</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">tweezers</td>
			<td style="width:180px;"></td>
			<td style="width:119px;">custom design</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">incubator</td>
			<td style="width:180px;">Heraeus Instruments GmbH</td>
			<td style="width:119px;">51008815</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">vortex mixer</td>
			<td style="width:180px;">Fisons</td>
			<td style="width:119px;">-</td>
			<td>Whirlimixer</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">centrifuge</td>
			<td style="width:180px;">Heraeus Instruments GmbH</td>
			<td style="width:119px;">75003360</td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">gamma well counter</td>
			<td style="width:180px;">MED Nuklear-Medizintechnik Dresden GmbH</td>
			<td style="width:119px;">-</td>
			<td>Isomed 2100</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">water for chromatography</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.15333.2500</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">acetonitrile for chromatography</td>
			<td style="width:180px;">Merck KGaA</td>
			<td style="width:119px;">1.00030.2500</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">trifluoroacetic acid</td>
			<td style="width:180px;">Sigma-Aldrich</td>
			<td style="width:119px;">91707</td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">TLC radioactivity scanner</td>
			<td style="width:180px;">raytest Isotopenmessger&#228;te GmbH</td>
			<td style="width:119px;">B00003875</td>
			<td>equipped with beta plastic detector</td>
		</tr>
	</tbody>
</table>

investigations on the ga(iii) complex of eob-dtpa and its 68ga radiolabeled analogue

We demonstrate a method for the isolation of EOB-DTPA (3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(ethoxybenzyl)-undecanedioic acid) from its Gd(III) complex and protocols for the preparation of its novel non-radioactive, i.e., natural Ga(III) as well as radioactive 68Ga complex. The ligand as well as the Ga(III) complex were characterized by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and elemental analysis. 68Ga was obtained by a standard elution method from a 68Ge/68Ga generator. Experiments to evaluate the 68Ga-labeling efficiency of EOB-DTPA at pH 3.8&#8211;4.0 were performed. Established analysis techniques radio TLC (thin layer chromatography) and radio HPLC (high performance liquid chromatography) were used to determine the radiochemical purity of the tracer. As a first investigation of the 68Ga tracers&#39; lipophilicity the n-octanol/water distribution coefficient of 68Ga species present in a pH 7.4 solution was determined by an extraction method. In vitro stability measurements of the tracer in various media at physiological pH were performed, revealing different rates of decomposition.

The ligand EOB-DTPA and the non-radioactive Ga(III) complex were analyzed via 1H and 13C{1H} NMR spectroscopy, mass spectrometry and elemental analysis. The results listed in Table 1 and depicted in Figures 1-6 verify the purity of the substances.
Elution of the 68Ge/68Ga generator yielded solutions of 400-600 MBq 68Ga. T...

Watch this Scientific Journal Video about Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue at JoVE.com

Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue

A procedure for the isolation of EOB-DTPA and subsequent complexation with natural Ga(III) and 68Ga is presented herein, as well as a thorough analysis of all compounds and investigations on labeling efficiency, in vitro stability and the n-octanol/water distribution coefficient of the radiolabeled complex.

Investigations on the Ga(III) Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue

We demonstrate a method for the isolation of EOB-DTPA (3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(ethoxybenzyl)-undecanedioic acid) from its Gd(III) ...

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