Experience with 68Ga-DOTATATE Preparation

Site

Number of cases (histology–neuroendocrine cancer)

1998–2002

2003–2007

1998–2007

Percentage of tumor of the site

Nasopharynx (ICD-9 147)

0.2

Esophagus (ICD-9 150)

0.7

Stomach (ICD-9 151)

0.9

Small intestine (ICD-9 152)

12.6

Colon (ICD-9 153)

1.1

Rectum and anus (ICD-9 154)

101

166

3.2

Liver (ICD-9 155)

0.3

Gall blabber and extrahepatic bile duct (ICD-9 156)

0.8

Pancreas (ICD-9 157)

2.8

Retroperitoneum and peritoneum (ICD-9 158)

0.7

Nasal cavities and sinuses (ICD-9 160)

3.4

Larynx (ICD-9 161)

0.4

Lung (ICD-9 162)

110

1.2

Thymus and mediastinum (ICD-9 164)

Skin excluding melanoma (ICD-9 173)

0.1

Female breast (ICD-9 174)

0.1

Cervix uteri (ICD-9 180)

0.9

Corpus uteri (ICD-9 182)

0.2

Ovary and uterine adnexa (ICD-9 183)

0.2

Vagina and vulva (ICD-9 184)

0.5

Prostate (ICD-9 185)

0.1

Bladder (ICD-9 188)

0.4

Other endocrine glands (ICD-9 194)

1.2

ICD International Classification of Disease

NETs are defined as epithelial neoplasms with predominant neuroendocrine differentiation, arising in most organs of the body (Modlin et al. 2008). NETs constitute a heterogeneous group of tumors that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs) (Kaltsas et al. 2005). At least five SSTR subtypes have been identified (SSTRs 1–5) (Reisine and Bell 1995). Of NETs, 70–90% express SSTR-2 and SSTR-5 (Papotti et al. 2002). Diagnosis of NET primaries and metastases is challenging, as these lesions are small in size with variation in many anatomical locations. Radiolabeled peptides bind to SSTR and provide in vivo histopathological information for diagnostic purposes (Signore et al. 2001). Peptides have fast clearance, rapid tissue penetration, and low antigenicity, features making them suitable as good targeting molecules for radiopharmaceuticals.

The commonest tracer for SPECT imaging is commercially available ¹¹¹In-DTPA-octreotide (¹¹¹In-Octreoscan^®) with detection sensitivity of 67–100% (Kaltsas et al. 2001, 2004). Diagnostic sensitivity of ¹⁸F-FDG is low for tumors with low proliferation index, slow growth rate, and low glucose consumption such as NETs (Adams et al. 1998; Belhocine et al. 2002). Many ⁶⁸Ga radiopharmaceuticals have been used for SSTR imaging. The efficiency of PET tracer ⁶⁸Ga-DOTATOC for detecting NETs is better than that of ¹¹¹In-Octreoscan^® (Buchmann et al. 2007). ⁶⁸Ga-DOTATOC is superior to ¹¹¹In-DTPA-octreotide in detecting small tumors and tumors with low-density SSTR expression (Kowalski et al. 2003). Superior imaging quality of PET is attributed to improved detection by ⁶⁸Ga-DOTATOC (Hofmann et al. 2001).

There is great interest in use of ⁶⁸Ga radiopharmaceuticals due to:

The availability of ⁶⁸Ga from a ⁶⁸Ge/⁶⁸Ga generator

Superior imaging quality of ⁶⁸Ga–SSTR analogs over ¹¹¹In-DTPA-octreotide

Potential to switch to therapy with ¹⁷⁷Lu and ⁹⁰Y (theranostics)

Possibility of the availability of cold kits

As an alternative PET radioisotope to cyclotron-based ¹⁸F⁻

As a PET equivalent to ^99mTc radiopharmaceuticals for SPECT.

The parent, ⁶⁸Ge with half-life of 270.8 days, is produced by accelerator. ⁶⁸Ga has half-life of 68 min and decays by ${{\upbeta}}_{\max }^{ + }$ of 1.92 MeV (89%) and electron capture (11%) (Maecke et al. 2005). A number of ⁶⁸Ge/⁶⁸Ga generator systems have been developed, with their unique advantages and disadvantages. The ⁶⁸Ga generator with calcinated hydrous tin dioxide column has been in use for many years with average yield of 65%. ⁶⁸Ge breakthrough was reported to be 6.1 × 10⁻⁴% (Aardaneh and van der Walt 2006).

⁶⁸Ga-DOTATATE has higher sensitivity for low-grade tumors and greater avidity to well-differentiated NETs than ¹⁸F-FDG, which shows greater avidity to poorly differentiated NETs (Kayani et al. 2008). ⁶⁸Ga-DOTATATE can identify additional lesions in patients with negative or equivocal ¹¹¹In-DTPA-octreotide scans. It shows good lesion recognition in low-grade tumors and changes clinical management in 70.6% of patients (Srirajaskanthan et al. 2010). ⁶⁸Ga-DOTATATE is superior to ¹⁸F-DOPA PET in evaluation of well-differentiated metastatic NETs (Haug et al. 2009).

The aim of this study is to determine feasibility of ⁶⁸Ga-DOTATATE application in routine clinical practice for PET imaging of NETs in a limited number of patients (n = 6).

2 Materials and Methods

2.1 DOTA-Tyr³-Octreotate

DOTA-Tyr³-octreotate was purchased commercially (DOTA-dPhe-Cys-Tyr-dTrp-Lys-Thr-Cys-Thr-OH; molecular formula: C₆₅H₉₀N₁₄O₁₉S₂; molecular weight: 1,435.6; purity (HPLC): >99%; peptide content: 86.8%). DOTATATE vials were prepared in house. A peptide vial contained 62.5 μg peptide, 0.25 mg gentisic acid, and 25 μL glacial acetic acid.

2.2 ⁶⁸Ge/⁶⁸Ga Generator

Gallium generator (30 mCi) was purchased from iThamba and eluted with 0.6 M HCl (ultrapure). The elution profile was determined with 0.5 mL fractions of 0.6 M HCl for 10 mL, upon receipt of the generator. The generator was pre-eluted 2 h prior to the radiolabeling process with 5 mL 0.6 M HCl to flush impurities. The generator was eluted with three fractions of 0.6 M HCl (first 1 mL, second 1.5 mL, third 7.5 mL; fractionation method). The second, 1.5 mL fraction was collected for radiolabeling, whereas the first and third fractions were discarded.

2.3 ⁶⁸Ga Radiolabeling

Generator eluate (second 1.5 mL, pH 1) was added to a peptide vial, and the pH of the solution was immediately adjusted to 3.8–4.0 by adding 1 M sodium acetate solution. The vial was heated to 95–100°C for 10 min. The reaction mixture was cooled down to room temperature, and the purification was completed with C18 Sep-Pak cartridge, eluted with 2 mL 99.7% ethanol. It was reformulated with 1 mL 4.4% EDTA plus 9 mL sterile water for injection and filtered through 0.22-μM Millipore filter. Quality control was performed by radio-TLC with 0.1 M sodium citrate as mobile phase and silica gel as stationary phase with RCP >95%. Synthesis was done manually.

2.4 Scan Procedure

⁶⁸Ga-DOTATATE (111–185 MBq, 3–5 mCi) was injected into patients with proven NET (n = 6), and 1 h post-injection scan was performed with 64-Slice GEMINI TF PET/CT. Patient studies were performed under a “name-patient permit” issued by the relevant regulatory authority.

3 Results and Discussion

3.1 Generator Elution Profile

The elution profile of the generator showed that the majority of activity was in the second, 1.5 mL fraction, while the first, 1.0 mL and third, 7.5 mL fractions contained negligible amounts of radioactivity (Fig. 1). This second, 1.5 mL fraction which contained the bulk of radioactivity was used for radiolabeling.

Fig. 1

a Elution profile of ⁶⁸Ge/⁶⁸Ga generator (x-axis, number of 0.5 mL fractions), b radioactivity contained in the first and second fractions

3.2 Post-Elution Processing

Metallic impurities in the generator eluate such as Zn^II from decay, Fe^III from the eluent, and metal ions from the generator column can greatly influence ⁶⁸Ga radiolabeling. Post-elution processing of generator eluate can be achieved by cation exchange column, anion exchange column, combination of cation and anion exchange columns, and fractionation method (Zhernosekov et al. 2007; Roesch and Riss 2010). A fractionation method reported in literature was used in this study (Breeman et al. 2005). Though this method cannot chemically remove the metallic impurities, it can minimize the impurity content.

Only gold members can continue reading. Log In or Register to continue