68Ga-autoclabeling of DOTA-TATE and DOTA-NOC.
ABSTRACT A new method combining (68)Ga-labeling and steam sterilization, here called autoclabeling, has been evaluated for two somatostatin receptor binding tracers used for positron emission tomography (PET) imaging of neuroendocrine tumors; DOTA-TATE and -NOC.
The two peptides DOTA-TATE and -NOC were labeled with (68)Ga by heating for 15 min at 121°C in the presence of acetate buffer at pH 4.3. The product solutions were tested for sterility, presence of endotoxins, degradation of peptide and osmolality.
Complete incorporation of (68)Ga was obtained after the autoclabeling reaction and no degradation of the peptides was observed. Sterility was verified and the presence of endotoxins was well within Ph. Eur limits (175IU/maximum injected volume).
The autoclabeling method provides a convenient procedure for (68)Ga-labeling by combining the labeling reaction and steam sterilization into one single step.
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ABSTRACT: Gallium-68 has the potential to become the technetium-99m of positron emission tomography with ideal decay characteristics and a long-lived parent isotope for generator production. The work in the area of 68Ga is focused on two key areas: (1) synthesis of a library of bifunctional chelators, which can be quickly radiolabelled to form kinetically inert complexes under mild conditions compatible with biomolecules and (2) development of radiosynthetic methodologies for clinical use and to facilitate radiolabelling of a wide range of chelators under mild conditions. Recent advances in these areas, with particular focus on the past 3 years, are covered herein.Journal of Labelled Compounds and Radiopharmaceuticals 02/2014; · 1.24 Impact Factor
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ABSTRACT: PURPOSE: The objective of this study is to determine the range of SUVmax of 68Ga-DOTATATE in normal organs and tumoral lesions and establish uptake unrelated to NET. MATERIALS AND METHODS: One hundred and twenty patients (57 men, 63 women), who underwent (68)Ga-DOTATATE PET/CT imaging in our institution were analyzed. Patients were indicated for (68)Ga-DOTATATE PET/CT imaging to detect primary tumor or metastasis of suspected or previously known NET, to determine SSTR positivity and to detect occult source of ectopic Cushing syndrome. Normal range of uptake was calculated for the organs that were proven to have no pathology by either conventional radiological imaging or clinical follow-up, using SUVmax as a semiquantitative measure. Uptake and tumor to background (T/B) ratios of tumoral lesions in liver, pancreas, bone, brain and lymph nodes were calculated. Uptakes due to lesions unrelated to NET were also documented. RESULTS: Significant uptake was found in spleen, kidneys, adrenal glands, liver and pituitary gland with mean SUVmax of 24.67, 14.30, 13.73, 9.12 and 9.74 respectively. Uptake was measured separately for the pancreatic head and body separately, however, besides a slightly heterogeneous uptake; the difference was not statistically significant. Uptake in the tumoral lesions had high (T/B) ratios with mean SUVmax of 28.72, 25.21, 18.28, 34.73 and 12.59 for liver, pancreas, bone, brain and lymph nodes, respectively. Incidental benign tumoral lesions were detected in 3 patients (2.5 %) which were meningioma and fibrous dysplasia demonstrating significant and breast fibroadenoma demonstrating mild (68)Ga-DOTATATE uptake. Non-neoplastic processes were detected in 4 patients (14.1 %), including postsurgical inflammation, reactive lymph nodes, arthritis and demonstrated faint to mild (68)Ga-DOTATATE uptake, with the exception of significant uptake in accessory spleen. CONCLUSION: (68)Ga-DOTATATE has high T/B ratio with physiological biodistribution comparable to its counterparts. However, the presence of SSTRs in benign and malignant lesions unrelated to NET may be challenging in interpretation particularly where the physiological uptake is variable.Annals of Nuclear Medicine 03/2013; · 1.41 Impact Factor
68Ga-Autoclabeling of DOTA-TATE and DOTA-NOC
Elisabeth Blom, Jacek Koziorowskin
Department of Clinical Physiology, 54 P1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
a r t i c l e i n f o
Received 4 November 2011
Received in revised form
8 March 2012
Accepted 19 March 2012
Available online 28 March 2012
a b s t r a c t
Introduction: A new method combining68Ga-labeling and steam sterilization, here called autoclabeling,
has been evaluated for two somatostatin receptor binding tracers used for positron emission
tomography (PET) imaging of neuroendocrine tumors; DOTA-TATE and -NOC.
Methods: The two peptides DOTA-TATE and -NOC were labeled with68Ga by heating for 15 min at
121 1C in the presence of acetate buffer at pH 4.3. The product solutions were tested for sterility,
presence of endotoxins, degradation of peptide and osmolality.
Results: Complete incorporation of
degradation of the peptides was observed. Sterility was verified and the presence of endotoxins was
well within Ph. Eur limits (175IU/maximum injected volume).
Conclusions: The autoclabeling method provides a convenient procedure for68Ga-labeling by combin-
ing the labeling reaction and steam sterilization into one single step.
68Ga was obtained after the autoclabeling reaction and no
& 2012 Elsevier Ltd. All rights reserved.
The use of
tracers is increasing, mainly due to their convenient preparation
using a68Ge/68Ga generator, eliminating the need for a considerably
more expensive cyclotron (R¨ osch and Knapp, 2003). Also, the68Ga
half-life, being 68 min, is an advantage with regard to radiation
dose for the patient and compatibility with the pharmacokinetics of
most peptides used for imaging (Breeman and Verbruggen, 2008).
Various synthetic analogs of somatostatin (SST, the somatotropin
release inhibiting factor) labeled with nuclides such as e.g.111In,
90Y,177Lu, and68Ga (Krenning et al., 1993; Waldherr et al., 2002;
Forrer et al., 2007; Gabriel et al., 2007; Hofmann et al., 2006;
Kowalski et al., 2003) have shown high potential for imaging and
treatment of somatostatin receptor (SSTR)-positive tumors and
their metastases mainly having neuroendocrine origin (Wild et al.,
2003) The SSTR has several major subtypes (1–5). Due to the
unequal distribution of the subtypes in SSTR-positive malignancies
(SSTR2 and SSTR5 being the most abundant in neuroendocrine
tumor cells) the structures of the somatostatin analogs are varied to
obtain high binding affinity (Reubi et al., 2000).
In some studies
shown considerably better pharmacological properties than the
such as111In-DTPA-octreotide (OctreoScan) which today is routi-
nely used (Krenning et al., 2003). The
68Ga-labeled positron emission tomography (PET)
68Ga-labeled octreotide derivatives have
111In-labeled peptides (Antunes et al., 2007),
azacyclododecane-1,4,7,10-tetrayl)tetraacetic acid), DOTA-TATE
(DOTA-Tyr3-octreotate) and DOTA-NOC (DOTA-1-Nal3-octreotide)
are today used for PET imaging of neuroendocrine tumors (Roesch
and Riss, 2010). DOTA-NOC was reported in 2003 to have high
affinity for the SSTR subtypes 2, 3 and 5 (Wild et al., 2003). DOTA-
TATE is known to have excellent affinity for SSTR2, but low or
nonexistent affinity for other SSTRs (Reubi et al., 2000).
In the present work we have explored a combination of
labeling and steam sterilization, here called autoclabeling, for
the68Ga-labeling of DOTA-TATE and -NOC. The method is investi-
gated with regard to radiolabeling, peptide stability, sterility,
presence of endotoxins, and osmolality.
2. Materials and methods
cyclic(2–7) disulfide) and DOTA-NOC (DOTA-1-Nal3-octreotide,
tryptophyl-L-lysyl-L-threonyl-N-[(1 R,2 R)-2-hydroxy-1-(hydroxy-
methyl)propyl]-, cyclic (2–7)-disulfide) were obtained from ABX
(Radeberg, Germany). Hydrochloric acid (30%) Suprapur and metha-
nol (Merck) were obtained from VWR (Herlev, Denmark). Water,
acetic acid and sodium acetate, all TraceSELECTsFluka Analytical,
Contents lists available at SciVerse ScienceDirect
journal homepage: www.elsevier.com/locate/apradiso
Applied Radiation and Isotopes
0969-8043/$-see front matter & 2012 Elsevier Ltd. All rights reserved.
nCorresponding author. Tel.: þ45 40248246; fax: þ45 44883411.
E-mail address: email@example.com (J. Koziorowski).
Applied Radiation and Isotopes 70 (2012) 980–983
and also citric acid and ammonium acetate were obtained from
Sigma-Aldrich (Brøndby, Denmark). A MillexsGV syringe driven
filter unit, Low Protein Binding Durapore, 0.22mm (Millipore,
Copenhagen, Denmark), was used for sterile filtering. The indicator
tape for steam sterilization (TimeMed Labeling System Inc.), used as
an indicator, was obtained from VWR (Herlev, Denmark). Headspace-
vials (10 mL, 46?22.5 mm), clear glass, 1st hydrolytic class, flat
bottom and 20 mm combination seal: aluminum crimp cap, silicone
white/PTFE beige, 451 shore A, 3.2 mm (La-Pha-Packs) from VWR
(Herlev, Denmark) were used. For HPLC, water from an in-house
Millipore Direct-QTMpurification system, acetonitrile LiChrosolvs
from Merck (VWR, Herlev, Denmark), and trifluoroacetic acid (TFA)
ReagentPlussfrom Sigma-Aldrich (Brøndby, Denmark) were used.
Alkoholswabs were obtained from Mediq (Aarhus, Denmark). Sterican
(0.9?25 mm, 20G 1) needles from BBraun were used. The purchased
chemicals were used without further purification.
2.2. Analytical methods
High Performance Liquid Chromatography (HPLC) analyses of
radiolabeled compounds were performed on a Shimadzu Ultra-Fast
Liquid Chromatogrphy (UFLC) system equipped with a SPD-M20A
Prominence Diode Array Detector, a LC-20AD Prominence Pump
and a radiodetector model 105S-1 (Carroll & Ramsey Associates,
Berkley, USA). A gradient with water (A) and acetonitrile (B), both
containing 0.1% TFA, as a mobile phase with UV detection at 220
and 254 nm was used, program (1); 5% B for 5 min, then up to 95%
in 5 min, flow 0.5 mL/min or program (2) 18% B for 2 min, then up
to 60% in 9 min and 60% for 3 min, flow 0.6 ml/min. A Luna 3u
C18(2) 100A (30 mm?4.60 mm, 3 mm) column (Phenomenex,
Allerød, Denmark) was used. Instant thin layer chromatography
(ITLC) was performed using Tec-control chromatography strips
(Biodex, NY, USA) and 0.2 M citric acid or ammonium acetate
(1 M)/methanol 1:1as the mobile phase. The ITLC strips were
analyzed on a Raytest miniGita TLC scanner.
2.3. Preparation of68Ga
68Ga (t½¼68 min, bþ¼89% and EC¼11%) was available from a
68Ge/68Ga generator system (ITG, Garching, GmbH, Germany,
was attached to a column based on an organic resin. The
generator is autoclaved during manufacturing and was validated
with respect to sterility and endotoxins. The68Ga was eluted with
0.05 M hydrochloric acid. The generator eluate was fractioned by
discarding the first 0.5 mL and collecting the next 1.5 mL for the
synthesis. The breakthrough of68Ge in the 1.5 mL was o0.001%
(measured on a Canberra GX2018 germanium detector), which is
well acceptable as free68Ge is rapidly excreted (Ando et al., 1989)
and even higher levels give neglible dose (?11 ppm of the total
dose;Konijenberg and Breeman, 2009).
68Ge radioactivity 1.7 GBq) in which
68Ge (T½¼270 d)
2.4. Labeling procedure
The eluted 1.5 mL
mixed with DOTA-TATE or -NOC (50 mg in 500 mL 0.2 M acetate
buffer, pH¼5.0) resulting in a total volume of 2 mL in a 10 mL
hydrolytic glass vial, in a Grade A hotcell. The pH of the final
solution was 4.3. The reaction was conducted in a heating block at
121 1C for 15 min (or 90 1C for 10 min for the test reactions),
where the vial was immersed in glycerin. For the labeling
reactions performed at 90 1C the reaction mixture was filtered
through a 0.22 mm filter, but not for the reactions performed at
121 1C. The septum was wiped with a sterilizing alcohol swab
prior to withdrawal of the QC sample which was analyzed by
HPLC and ITLC. HPLC retention times for68Ga-labeled products;
68Ga solution (in 0.05 M HCl (aq)) was
program (1): DOTA-TATE; rt: 7.65 min, DOTA-NOC; rt: 7.80 min,
and program (2) DOTA-TATE; rt: min, DOTA-NOC; rt: 10.21 min.
Rfvalues on ITLC (citric acid): DOTA-TATE and -NOC ?0.1; free
68Ga ?0.9; (ammonium acetate/methanol): DOTA-TATE and
-NOC ?0.9; colliodalþfree68Ga ?0.1.
2.5. Test of sterility procedure
SterilAmpssolution sterilization biological indicators (http://
www.sgmbiotech.com/products/sterilamp.php) containing spores
of Geobacillus stearothermophilus (Bozeman, USA), which is also
described as a suitable biological indicator for steam sterilization
in the European Pharmacopoeia (Ph. Eur., 7.0, 5.1.2, 2010), were
used as indicators for a correctly performed sterilization process.
Five ampoules were placed inside a 10-mL reaction vial and
heated to 121 1C for 15 min and five ampoules inside a 10-mL
reaction vial were heated to 90 1C for 10 min for control together
with the 2 mL reaction mixture. The indicator ampoules were
thereafter incubated at 55–60 1C for test of growth of spores.
2.6. Sterility test of product solution
The sterility of the68Ga-labeled product solutions of DOTA-
TATE and –NOC was tested in a Fluid thioglycollate medium and a
Soya-bean casein digest medium which were incubated for 14
days at 30–35 1C and 20–25 1C respectively.
2.7. Test for endotoxins
Tests for the presence of endotoxins were performed using a
Charles River Endosafes-PTSTMinstrument. The samples were
diluted 1:1 with an endotoxin free 0.25 M TRIS base solution
(pH 9, Charles River Laboratories), giving a final pH of 7, prior to
use in the instrument.
The osmolality of the product solutions was determined using
a Knauer Semimicro-Osmometer K-7400.
3. Results and discussion
DOTA-TATE and -NOC conjugates were labeled with68Ga using
a hydrochloric acid solution of the radiometal eluted from the
68Ge/68Ga generator system. The68GaCl3used was in conformity
Fig. 1. Schematic drawing of the reaction setup with the reaction vial immersed in
glycerin in the heating block.
E. Blom, J. Koziorowski / Applied Radiation and Isotopes 70 (2012) 980–983
with the Ph. Eur. draft monograph (Ph. Eur., 2011a). An acetate
buffer (0.2 M, pH¼5.0) was used, to give a resulting pH of 4.3, for
the reaction mixture. The labeling reaction was performed at
121 1C for 15 min, as specified for preparation of sterile products
in Ph. Eur. (Ph. Eur. 7.0, 5.1.1, 2010), without subsequent sterile
filtration, or at 90 1C for 10 min for reference labeling reactions,
with subsequent sterile filtration. A conventional heating block, in
which the reaction vial was immersed into glycerin, was used as
the heating source, where the steam sterilization occurred inside
the vial. A schematic drawing of the setup is shown in Fig. 1.
In each synthesis 50 mg of the peptide was used, since this
amount has been reported to give the highest tumor-to-back-
ground contrast in PET images for DOTA-TOC (Velikyan et al.,
2010). After complete reaction the mixture was analyzed by HPLC
and ITLC. Complete incorporation of
differences in appearance of the HPLC chromatograms for either
UV or radioflow detectors, using two different HPLC programs
((1) and (2)), were observed. Thus no degradation of the peptides
occurred at high reaction temperature. As an example, the chro-
matograms for the labeling reactions performed at 90 1C for 10 min
and 121 1C for 15 min for DOTA-NOC, using the slower gradient
(program (2)) as described in Ph. Eur., are shown in Fig. 2.
The68Ga autoclabeling synthesis including subsequent HPLC
analysis was accomplished within 25 min. No differences in68Ga
incorporation were observed between the two peptides. The
radiochemical yield was 7773% (n¼6; non-decay-corrected).
When performing the labeling reaction in the classical way with
10 min heating at 90 1C with subsequent sterile filtration
(0.22 mm filter) the radiochemical yield was 5873% (n¼5). The
specific radioactivity (end-of-synthesis) was 1474 GBq/mmol
starting from 6007100 MBq (n¼6) for both tracers using the
autoclabeling method. Due to the facts that acetate buffer is
approved for injection in humans, the absence of free68Ga in the
product solution, and that the product had already been auto-
claved, there was no need for purification of the product after the
synthesis. The ITG generator contains a novel germanium-speci-
fic, organic, pyrogallol-based resin, designed to give a low Ge-68
breakthrough. We have validated and revalidated the generator
with respect to Ge-68 breakthrough and not found levels above
0.001% Ge-68 in the eluate.
The purpose of combining steam sterilization and labeling into
autoclabeling is to save synthesis time by removing the need for
autoclaving or sterile filtering after completed labeling reaction,
and also to avoid the loss of labeled product on the sterile filter. In
general, when working with short-lived isotopes, the goal is to
reach the highest possible yield, through the shortening of the
68Ga was obtained. No
In order to validate the steam sterilization procedure, five
SterilAmp ampoules were placed inside a 10-mL reaction vial
together with the 2 mL reaction mixture. The result was negative
for growth of spores after 48 h, which confirms the efficiency of
the steam sterilization procedure. For control of growth of spores
five of the ampoules were also heated at 90 1C for 10 min, giving a
positive result for growth of spores after 48 h. SterilAmp is a self-
contained unit for monitoring steam sterilization of liquids.
The steam sterilization procedure was further confirmed by
the use of indicator tape applied to the outside of the reaction
vial. Sterility of the product solutions was tested in the growth
medium and no growth was detected. The endotoxin content was
o0.2 EU/mL for both DOTA-TATE and -NOC product solutions,
which is well within the Ph. Eur. limit. Due to the low pH of the
solutions, they were buffered to pH 7 to be compatible with the
Charles River PTS system. The osmolality of the product solutions
of DOTA-TATE and -NOC was 314 and 298 mOsmol/kg, respec-
tively (cf. saline 290 mOsmol/kg).
To determine if particulate matter was formed in the labeling
reaction at 121 1C, the product solutions from labeling reactions at
90 1C and 121 1C for both tracers were passed through sterilization
filters, and the amount of radioactivity remaining on the filter
measured. On average, 25% of the radioactivity remained in the
filter for both tracers and temperatures. For further investigation of
presence of68Ga in colloidal form, the ITLC method described in
the draft monograph, with ammonium acetate/methanol as the
mobile phase, was used. The analyses showed no sign of68Ga in
colloidal form being formed. Also experiments where68GaCl3in
HCl was heated at 121 1C together with only the acetate buffer
were performed. The reaction mixture was analyzed by ITLC with
citric acid mobile phase in which any colloidal form of68Ga would
have an Rfvalue of 0.1. No radioactive compound with Rf?0.1 was
observed. These results indicated that no particulates were formed.
To summarize, the68Ga-labeled DOTA-TATE and -NOC product
solutions were in agreement with the standards stated in the
Ph. Eur. draft monograph for DOTA-TOC (Ph. Eur. 2011b).
The autoclabeling method provides a convenient procedure for
68Ga-labeling by combining the labeling reaction and steam
sterilization into one single step. The total synthesis time is
shortened, leading to lower loss of radioactivity by decay and
thereby higher specific radioactivity. A sterile68Ga-labeled pro-
duct is obtained within 25 min, including HPLC analysis, ready for
injection in patients. Additionally, as the product is terminally
Fig. 2. HPLC chromatograms (program (2)) and overlay of UV 254 nm (blue, PDA Multi 1) and radioflow detector (red, AD 2) chromatograms; labeling of DOTA-NOC at (a)
90 1C b) at 121 1C. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
E. Blom, J. Koziorowski / Applied Radiation and Isotopes 70 (2012) 980–983
sterilized in its final container, it opens up the possibility for
parametric release (Ph. Eur., 7.0, 5.1.1, 2010; CPMP/QWP/3015/99,
2001). To the best of our knowledge, this is one of the first68Ga-
labeling methods which mimic the
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