Improved safety and efficacy of Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with L-lysine.

Background: Targeted alpha therapy (TAT) offers advantages over current β-emitting conjugates for peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. PRRT with Lu-DOTATATE or Y-DOTATOC has shown dose-limiting nephrotoxicity due to radiopeptide retention in the proximal tubules. Pharmacological protection can reduce renal uptake of radiopeptides, e.

Radiolabeling of DOTA-like conjugated peptides with generator-produced (68)Ga and using NaCl-based cationic elution method.

Gallium-68 ((68)Ga) is a generator-produced radionuclide with a short half-life (t½ = 68 min) that is particularly well suited for molecular imaging by positron emission tomography (PET). Methods have been developed to synthesize (68)Ga-labeled imaging agents possessing certain drawbacks, such as longer synthesis time because of a required final purification step, the use of organic solvents or concentrated hydrochloric acid (HCl). In our manuscript, we provide a detailed protocol for the use of an advantageous sodium chloride (NaCl)-based method for radiolabeling of chelator-modified peptides for molecular imaging.

Influence of tumour size on the efficacy of targeted alpha therapy with (213)Bi-[DOTA(0),Tyr(3)]-octreotate.

Background: Targeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. (213)Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether (213)Bi-[DOTA(0), Tyr(3)]-octreotate ((213)Bi-DOTATATE), a (213)Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR2), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR2 in comparison to its effectiveness for smaller tumours.

Alternative method to determine Specific Activity of (177)Lu by HPLC.

Unlabelled: Peptide Receptor Radionuclide Therapy (PRRT) with (177)Lu-DOTA-peptides requires (177)Lu with high specific activity (SA) and values >740 GBq (177)Lu per mg Lu to maximise the atom% of (177)Lu over total Lu. Vendors provide SA values which are based on activity and mass of the target, whereas due to "burn-up" of target, these SA values are not accurate. For a radiochemist the SA of (177)Lu is of interest prior to radiolabeling.

Accurate assessment of whole-body retention for PRRT with (177)Lu using paired measurements with external detectors.

The aim of this study was to assess the accuracy of the results of whole-body measurements by comparison with the urine collection method in the PRRT with (177)Lu and furthermore to develop a more accurate method of paired measurements. Excreted samples were collected at given intervals and activities were measured by a dose calibrator. Traditionally, whole-body activities during subsequent measurements are normalized individually to the administered activity.

Overview of Development and Formulation of ¹⁷⁷Lu-DOTA-TATE for PRRT.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has become an established procedure for the treatment of patients suffering from inoperable neuroendocrine cancers over-expressing somatostatin receptors. Success of PRRT depends on the availability of the radiolabeled peptide with adequately high specific activity, so that required therapeutic efficacy can be achieved without saturating the limited number of receptors available on the target lesions. Specific activity of the radionuclide and the radiolabeled somatostatin analog are therefore an important parameters.

Application of single-vial ready-for-use formulation of 111In- or 177Lu-labelled somatostatin analogs.

For the sake of safety it would be desirable to store and transport the ready-for-use liquid formulation (diagnostics and therapeutics) of radiolabelled peptides. The use of ethanol, in combination with a mixture of gentisic- and ascorbic acid, has superior effects on stabilizing radiolabelled somatostatin analogs. As a consequence, (111)In- and (177)Lu-labelled somatostatin analogs can be stored and transported in a single-vial ready-for-use liquid formulation up to 7 days after radiolabelling.

Reversed phase free ion selective radiotracer extraction (RP-FISRE): a new tool to assess the dynamic stabilities of metal (-organic) complexes, for complex half-lives spanning six orders of magnitude.

This paper introduces reversed phase free ion selective radiotracer extraction (RP-FISRE) as a new tool to assess the stability of metal complexes, as illustrated by the assessment of the stability of [(177)Lu]Lu-DOTA-octreotate. To this end, the TUDelft-developed FISRE, where the released metal is column-retained and the complex eluted, was changed into RP-FISRE, where the complex is column-retained and the released metal is eluted. This change in the approach allows for studies to be performed with high stability complexes.

Effectiveness of quenchers to reduce radiolysis of (111)In- or (177)Lu-labelled methionine-containing regulatory peptides. Maintaining radiochemical purity as measured by HPLC.

An overview how to measure and to quantify radiolysis by the addition of quenchers and to maintain Radio-Chemical Purity (RCP) of vulnerable methionine-containing regulatory peptides is presented. High RCP was only achieved with a combination of quenchers. However, quantification of RCP is not standardized, and therefore comparison of radiolabelling and RCP of regulatory peptides between different HPLC-systems and between laboratories is cumbersome.

Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview.

For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre-Coated Iodo-Gen(®) tubes and Iodo-Beads(®) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues.

The untapped potential of Gallium 68-PET: the next wave of ⁶⁸Ga-agents.

(68)Gallium-PET ((68)Ga-PET) agents have significant clinical promise. The radionuclide can be produced from a (68)Ge/(68)Ga generator on site and is a convenient alternative to cyclotron-based PET isotopes. The short half-life of (68)Ga permits imaging applications with sufficient radioactivity while maintaining patient dose to an acceptable level.

A new automated NaCl based robust method for routine production of gallium-68 labeled peptides.

A new NaCl based method for preparation of gallium-68 labeled radiopharmaceuticals has been adapted for use with an automated gallium-68 generator system. The method was evaluated based on 56 preparations of [(68)Ga]DOTATOC and compared to a similar acetone-based approach. Advantages of the new NaCl approach include reduced preparation time (<15 min) and removal of organic solvents.

Simplified NaCl based (68)Ga concentration and labeling procedure for rapid synthesis of (68)Ga radiopharmaceuticals in high radiochemical purity.

A simple sodium chloride (NaCl) based (68)Ga eluate concentration and labeling method that enables rapid, high-efficiency labeling of DOTA conjugated peptides in high radiochemical purity is described. The method utilizes relatively few reagents and comprises minimal procedural steps. It is particularly well-suited for routine automated synthesis of clinical radiopharmaceuticals.

Scaled-up radiolabelling of DOTATATE with 68Ga eluted from a SnO2-based 68Ge/68Ga generator.

A scaled-up radiolabelling and improved post-labelling purification procedure for [(68)Ga]DOTATATE is reported, using a more than 1 year old SnO(2)-based 1850MBq (68)Ge/(68)Ga generator (initially double-loaded with 3700MBq (68)Ge) as a source of ionic (68)Ga. The elution method of choice comprised elution with 0.6M HCl in a single 4mL fraction, containing up to 95% of the total eluted (68)Ga activity.

(68)Ga-labeled DOTA-peptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives.

In this review we give an overview of current knowledge of (68)Ga-labeled pharmaceuticals, with focus on imaging receptor-mediated processes. A major advantage of a (68)Ge/(68)Ga generator is its continuous source of (68)Ga, independently from an on-site cyclotron. The increase in knowledge of purification and concentration of the eluate and the complex ligand chemistry has led to (68)Ga-labeled pharmaceuticals with major clinical impact.

Comparison of the binding and internalization properties of 12 DOTA-coupled and ¹¹¹In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607.

Purpose: Specific overexpression of cholecystokinin 2 (CCK2)/gastrin receptors has been demonstrated in several tumours of neuroendocrine origin. In some of these cancer types, such as medullary thyroid cancer (MTC), a sensitive diagnostic modality is still unavailable and therapeutic options for inoperable lesions are needed. Peptide receptor radionuclide therapy (PRRT) may be a viable therapeutic strategy in the management of these patients.

Reduction of Ge activity containing liquid waste from Ga PET chemistry in nuclear medicine and radiopharmacy by solidification.

PET with Ga from the TiO- or SnO- based Ge/Ga generators is of increasing interest for PET imaging in nuclear medicine. In general, radionuclidic purity (Ge vs. Ga activity) of the eluate of these generators varies between 0.

Characteristics of SnO2-based 68Ge/68Ga generator and aspects of radiolabelling DOTA-peptides.

Objectives: PET scintigraphy with (68)Ga-labelled analogs is of increasing interest in Nuclear Medicine and performed all over the world. Here we report the characteristics of the eluate of SnO(2)-based (68)Ge/(68)Ga generators prepared by iThemba LABS (Somerset West, South Africa). Three purification and concentration techniques of the eluate for labelling DOTA-TATE and concordant SPE purifications were investigated.

Optimised labeling, preclinical and initial clinical aspects of CCK-2 receptor-targeting with 3 radiolabeled peptides.

Medullary thyroid carcinoma (MTC) expresses CCK-2 receptors. (111)In-labeled DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2) (DOTA-MG11), DOTA-DAsp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH(2) (DOTA-CCK), and (99m)Tc-labeled N(4)-Gly-DGlu-(Glu)(5)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2) ((99m)Tc-Demogastrin 2) are analogs developed for CCK-2 receptor-targeted scintigraphy. All 3 radiolabeled analogs were selected on the basis of their high CCK-2 receptor affinity and their good in vitro serum stability, with in vitro serum t(1/2) values of several hours.

Lanthanide(III) complexes of bis(phosphonate) monoamide analogues of DOTA: bone-seeking agents for imaging and therapy.

Lanthanide complexes of DOTA derivatives 2a (BPAMD) and 2b (BPAPD), having a monoamide pendant arm with a bis(phosphonate) moiety, were comparatively tested for application in MRI, radiotherapy, and bone pain palliation. (1)H, (31)P, and (17)O NMR spectroscopy show that they are nine-coordinated, with one water molecule in the first coordination sphere of the Ln(III) ion. The bis(phosphonate) moieties are not coordinated to the lanthanide and predominantly mono- and diprotonated at physiological pH.

Five Stabilized 111In-labeled neurotensin analogs in nude mice bearing HT29 tumors.

Neurotensin (NT) receptors are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity have been synthesized by replacing arginine residues with lysine and arginine derivatives. The aim of this study was to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer.

Radiolabelling DOTA-peptides with 68Ga.

Purpose: A new field of interest is the application of 68Ga-labelled DOTA-conjugated peptides for positron emission tomography (PET). The commercially available or house-made generators require time-consuming and tedious handling of the eluate. Radiolabelling at high specific activities without further purification is not possible, while high specific activities are necessary for peptides that potentially display pharmacological side-effects.

Reduction of skeletal accumulation of radioactivity by co-injection of DTPA in [90Y-DOTA0,Tyr3]octreotide solutions containing free 90Y3+.

Peptide receptor-targeted radionuclide therapy is nowadays being performed with radiolabeled DOTA-conjugated peptides, such as [90Y-DOTA0,Tyr3]octreotide (also known as OctreoTher or 90Y-DOTATOC). The incorporation of 90Y3+ is typically > or = 99%, however, since a total patient dose can be as high as 26 GBq or 700 mCi the amount of free 90Y3+ (= non-DOTA-incorporated) can be substantial. Free 90Y3+ accumulates in bone with undesired radiation of bone marrow as a consequence.

Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities.

DOTA-conjugated peptides, such as [DOTA(0),Tyr(3)]octreotide (DOTATOC) and [DOTA(0),Tyr(3)]octreotate (DOTA-tate), can be labelled with radionuclides such as (90)Y, (111)In and (177)Lu. These radiolabelled somatostatin analogues are used for peptide receptor radionuclide therapy (PRRT). Radioligands for PRRT require high specific activities.