A comparative study of 131I and 177Lu labeled somatostatin analogues for therapy of neuroendocrine tumours

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Abstract

This work analysed the influence of the chelating group and radioligand on somatostatin analogues in vivo and in vitro properties. The presence of DOTA in the radioiodinated peptide produced a labeled analogue with similar blood kinetics and biodistribution to 177Lu-DOTATATE and with lower abdominal uptake than 131I-TATE. In addition, 131I-DOTATATE showed significative tumour uptake, despite not so persistent after 24 h. 131I-DOTATATE can represent a cost-effective alternative to lutetium labeled peptide for neuroendocrine tumours therapy.

Introduction

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms which are characterised by the ability to produce biogenic amines and polypeptide hormones. These tumours come from endocrine glands, like pancreas, and usually origin metastases in the respiratory and gastrointestinal tract (Rufini et al., 2006).

In recent years, a number of new developments in targeted therapies have emerged (Oyen et al., 2007) and the presence of peptide receptors and transporters at the cell membrane of several NETs constitutes the basis of the clinical use of specific radiolabeled ligands. Because the majority of NETs express somatostatin receptors (SSTr), the introduction of radiolabeled somatostatin (SST) analogues for peptide receptor imaging and radiotherapy of neuroendocrine cancer have become a primary focus of interest in nuclear medicine (Kreening et al., 1992).

In order to visualise SST receptor-containing tumours, a long-acting SST analogue was required because the native SST has a half-life in blood of only 3 min due to rapid enzymatic degradation (Lamberts et al., 1987). Many efforts were made in order to find a radiolabeled selective analogue with a longer duration of action using synthetic SST peptide derivatives.

123I-labeling Tyr3-octreotide (Tyr-OC) was the first compound to be used for imaging of SST receptor-positive tumours in animals. However, some properties limited the use of this radiopharmaceutical, like relative low radiochemical yield and high uptake on liver and intestines after 30 min of the administration (Bakker et al., 1990).

Octreotide has been conjugated with diethylene-triamine-pentaacetic acid (DTPA) and labeled with 111In, showing an improved biodistribution when compared with the initial analogue. Today, 111In-DTPA-D-Phe1-octreotide has become the dominant radiolabeled SST analogue for visualisation of SSTr-expressing tumours (Kreening et al., 1992; Kwekkeboom et al., 2001).

Octreotide has been also conjugated with the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid), resulting in tracers that are suitable for a variety of clinical applications. In addition, replacement of C-terminal threonil of the octapeptide with the natural amino acid threonine, changing octreotide to octreotate, increased SSTr-2 affinity and tumour uptake (Kwekkeboom et al., 2001).

SST analogues also can be labeled with beta-emitting therapeutic radioisotopes. Newer therapeutic approaches involve the use of the beta-emitter yttrium-90 conjugated via DOTA to Tyr-OC. The therapeutic potential of 90Y-DOTA-Tyr-OC has been evaluated in some clinical protocols (Bodei et al., 2003; Waldherr et al., 2002) representing a remarkable therapeutic drug and an effective alternative to chemo and biotherapies. However, kidney toxicity remains the major concern in repeated administrations.

Alternatively to 90Y, 6.7 day half-life 177Lu has emerged as a promising short-range β emitter for target radiotherapy. The mean range of 177L β particles (max=497 keV) is 670 μm, making this radionuclide ideal for treating micro-metastatic disease. Because it also emits γ rays (208 keV, 11% abundance), imaging of 177Lu labeled endoradiotherapeutic agents is possible (Zalutsky, 2003).

The therapeutic potential of 177Lu labeled SST analogues was evaluated in comparative studies with either 111In or 90Y labeled molecules (Kwekkeboom et al., 2001; de Jong et al., 2005).

The SST analogue DOTA-Tyr3-octreotate (DOTATATE) has a ninefold higher affinity for the SSTr subtype 2 as compared with DOTA-Tyr-OC. Labeled with 177Lu, this compound was shown to be very successful in achieving tumour regression (Kwekkeboom et al., 2003; Forrer et al., 2005). In addition, SST derivatives labeled with 90Y and 177Lu can be combined to treat patients with tumours of various sizes with non-homogenous receptor distribution, to achieve higher cure rates (de Jong et al., 2005).

Despite good clinical therapeutical results obtained with 90Y and 177Lu labeled SST derivatives, these radionuclides are not easily available. 90Y are produced by high cost 90Sr-90Y generator while 177Lu only can be obtained in adequate specific activity by thermal neutron bombardment using enriched targets in medium to high flux reactor, making the production of 177Lu restricted (Pillai et al., 2003).

131I, with a half-life of 8.1 days, has been the most frequently used radionuclide for therapeutic applications, and has a mean range of 910 μm. Although 131I has a tissue range that is well suited to the treatment of small tumours, it also emits a 364 keV γ ray in 81% abundance which is not ideal for conventional or single photon emission tomographic imaging devices (Zalutsky, 2003).

The experience gained with radioiodinated SST ligands showed that the diagnostic and therapeutic usefulness of them was limited by their unfavourable kinetics, in vivo deiodination and resulting dosimetry. Additionally, they exhibited low tumour retention, which was often attributed to fast intracellular degradation of the tracers and subsequent extracellularisation (Wester et al., 2002; Bakker et al., 1996).

DOTA chelating group are not involved in the radioiodination of DOTATATE. Labeling occurs by the introduction of the radioiodine in the aromatic residue of tyrosine like in the labeling of Tyr3-octreotate (TATE) with radioiodine. However, the presence of the DOTA chelating group may change the lipophilicity of the peptide itself and influence in the stability and biological distribution of the radioiodinated peptide.

In this work, we optimised the labeling of DOTATATE and TATE with 131I and the labeling of DOTATATE with 177Lu to produce high radiochemical yield radiopharmaceuticals and evaluate the influence of the chelating group and of the radioligand on in vitro stability and in vivo behaviour of the SST labeled derivatives.

Section snippets

Reagents

DOTATATE was provided by piChem and the TATE by Anaspec (EUA). Na131I and 177LuCl3 were obtained from Nordion (Canada) and IBD (Holland), respectively. All other reagents were purchased from Sigma-Aldrich.

Labeling of TATE and DOTATATE with radioiodine (131I)

The labeling of TATE and DOTATATE with Na131I was optimised using Chloramine T method (Breeman et al., 2001). A solution of 10 μg of peptide in 40 μL of PBS (0.1 M phosphate-buffered saline pH 7.5) was transferred to a reaction vial. After the addition of the Chloramine T solution (5 μg/5 μL) and

Labeling of TATE and DOTATATE with radioiodine (131I)

Different molar peptide to radionuclide ratios were investigated in order to obtain mono-iodinated peptides to be applied in the biodistribution studies, considering that the di-iodinated peptide no longer binds to the SSTr, as previously reported (Bakker et al., 1996).

Electrophoresis analysis showed radiochemical purity of 98.4±0.3% for 131I-TATE and 95.4±0.5 for 131I-DOTATATE in a molar peptide to radionuclide ratio of 2.73. After Sep-Pak purification procedure, the radiochemical purity

Discussion

177Lu-DOTATATE has been applied in clinical protocols for therapy of neuroendocrine tumours (Kwekkeboom et al., 2003; Forrer et al., 2005; de Jong et al., 2005). The favourable biodistribution kinetic of the compound, that presents fast blood clearance, results in rapid and effective uptake in the tumour. The compound is mainly excreted by the kidneys, which constitutes the target organ for dosimetric considerations.

The physical properties of the 177Lu are particularly attractive to irradiate

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