Current Radiopharmaceuticals - Volume 8, Issue 2, 2015

Lutetium-177 (177Lu) is a late entrant into the nuclear medicine therapy arena but is expected to become one of the most widely used therapeutic radionuclides. This paper analyses the reason for the increasing preference of 177Lu as a therapeutic radionuclide. While the radionuclidic properties favor its use for several therapeutic applications, the potential for large scale production of 177Lu is also an important aspect for its acceptability as a therapeutic radionuclide. This introductory discussion also summarizes some developing clinical uses and suggested future directions for applications of 177Lu.

A short overview of fundamental chemistry of lutetium and of structural characteristics of lutetium coordination complexes, as relevant for understanding the properties of lutetium-177 radiopharmaceuticals, is presented. This includes basic concepts on lutetium electronic structure, lanthanide contraction, coordination geometries, behavior in aqueous solution and thermodynamic stability. An illustration of the structure and binding properties of the most important chelating agents for the Lu3+ ion in aqueous solution is also reported with specific focus on coordination complexes formed with linear and macrocyclic polydentate amino-carboxylate donor ligands.

Two methods of Lu-177 production are reviewed: irradiation of isotopically enriched Lu- 176 (direct way) and irradiation of ytterbium enriched with Yb-176 (indirect way). Based on neutronphysical calculations Lu-177 yield and specific activity were estimated for both methods. Lu-177 specific activity strongly depends on neutron flux density in the direct way, that is 75,000 Ci/g for 10- days irradiation in a neutron flux of 2.1015 cm-2s-1, and only 13,000 Ci/g after 30 days irradiation at neutron flux 1.1014 cm-2s-1. Irradiation of Yb-176 provides Lu-177 specific activity close to theoretical value (110,000 Ci/g). Neutron flux density effect Lu-177 yield, that is 530 Ci/g for 2.1015 cm-2s-1 neutron flux density after 30 days irradiation. A procedure of isolation and purification of Lu-177 from irradiated targets is described based on combination of galvanostatic extraction of ytterbium followed by cation-exchange chromatography from alfa-hydroxyisobutirate solutions on BioRad AG®50W-X8 resin.

This article presents a concise review of the production of no-carrier-added (NCA) 177Lu by the ‘indirect’ route by irradiating ytterbium-176 (176Yb)-enriched targets. The success of this production method depends on the ability to separate the microscopic amounts of NCA 177Lu from bulk irradiated ytterbium targets. The presence of Yb+3 from the target in the final processed 177Lu will adversely affect the quality of 177Lu by decreasing the specific activity and competing with Lu+3 complexation since ytterbium will follow the same coordination chemistry. Ytterbium and lutetium are adjacent members of the lanthanide family with very similar chemical properties which makes the separation of one from the other a challenging task. This review provides a summary of the methods developed for the separation and purification of NCA 177Lu from neutron irradiated 176Yb-enriched targets, a critical assessment of recent developments and a discussion of the current status of this 177Lu production method.

Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTA-peptides requires 177Lu with high specific activity (SA) and values >740 GBq 177Lu per mg Lu to maximise the atom% of 177Lu 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 177Lu is of interest prior to radiolabeling. An alternative method to determine SA was developed by HPLC, which includes a metal titration of a known amount of DOTA-peptide with a known amount of activity (177Lu), and a unknown amount of metal (177+natLu). Based on an HPLC separation of radiometal-DOTA-peptide and DOTA-peptide, and the concordant ratio of these components the metal content (177+natLu) can be calculated, and eventually the SA of 177Lu can be accurately determined. These experimentally determined SA values exceeded the estimated values provided by vendors by 27±16%, (range 6-73 %). The deviation of SA values for samples from the same Lu batch was <2% (n≥10). In conclusion: the SA of 177Lu is apparently often higher as stated by vendors in comparison to the experimentally determined actual values. For this reason, the SA of 177Lu-DOTA-TATE and other Lu-DOTA-peptides could be increased accordingly.

Lutetium-177 is a widely used therapeutic radionuclide in targeted therapy and it is important to know its specific activity at the time of radiopharmaceutical preparation, especially for radiolabeling peptides. However, there are no direct methods for the experimental determination of the specific activity which can be readily applied in a hospital radiopharmacy. A new technique based on the ‘saturation assay’ principle using DOTA as the binding agent for the estimation of specific activity of 177Lu is reported. The studies demonstrate the proof of principle of this new assay technique. The method is general and can be modified and applied for the estimation of specific activity of other metallic radionuclides by using DOTA or other suitable chelating agents.

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 177Lu 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. In order to correct for the effects of the activity in the bladder during the baseline measurement before the first voiding and activity redistributions in the patient body during subsequent measurements, a series of paired measurements before and after each voiding were carried out. Time-dependent detector responses at given times were derived and time-activity retentions were then determined. Compared to the results of the urine collection, whole-body activities by traditional whole-body measurements were overestimated by ca. 14% at 1 h after administration and randomly varied from -29% to 49% at 24 h. Measurement uncertainties of whole-body activities were from ±4% (the coverage factor k=2) at 1 h to >±20% at 24 h by the urine collection and ±7% by paired measurements, respectively. Whole-body activities at 1 h by paired measurements were validated using the results by measurements of the collected first urine. The new method of paired measurements has an equivalent measurement accuracy and even better during the later measurements with respect to the urine collection method and therefore can replace urine approach for assessing the time-activity remaining in the patient body.

This review mainly focuses on the dosimetry methodology which includes consideration of the number and time points of scans, imaging methodology, methods for integrating time-activity curves and calculating absorbed doses. 177Lu-labelled compounds show many advantages for dosimetry assessments due to attractive physical properties which comprise low abundance of photons for sufficient post-therapy imaging, a clearly separated gamma peak at 208 keV, and a low range of beta particles. The most up-to-date results of absorbed dose calculations for the kidneys, bone marrow, and tumors are provided. The absorbed doses reported for radiopeptide therapies using 177Lu labelled compounds taken from clinical studies show a high variability, presumably because of the different applied methodologies.

Lutetium-177 (177Lu) is a rare earth metal in the lanthanides series which decays by beta emission with a half life of 6.647 days to three excited states and the ground state of 177Hf. When 177Lu is produced by neutron capture in 176Lu, inevitably an admixture is formed of the long-lived isomer 177mLu. As its half-life of 160.4 days is so much longer than that of 177Lu, concerns are raised on its possible enhancement in radiation dose to the patient treated with 177Lu-DOTA-octreotate. This report evaluates this possible enhancement of the absorbed dose, based on the published pharmacokinetic profile of 177Lu-DOTA-octreotate and assuming an admixture of 1 kBq 177mLu /MBq 177Lu (0.1%).

Gold nanoparticles (AuNPs) have been proposed for a variety of medical applications such as localized heat sources for cancer treatment and drug delivery systems. The conjugation of peptides to AuNPs produces stable multimeric systems with target-specific molecular recognition. Lutetium- 177 (177Lu) has been successfully used in peptide radionuclide therapy. Recently, 177Lu-AuNPs conjugated to different peptides have been proposed as a new class of theranostic radiopharmaceuticals. These radioconjugates may function simultaneously as molecular imaging agents, radiotherapy systems and thermal-ablation systems. This article covers advancements in the design, synthesis, physicochemical characterization, molecular recognition assessment and preclinical therapeutic efficacy of gold nanoparticles radiolabeled with 177Lu and conjugated to RGD (-Arg-Gly-Asp-), Lys3-Bombesin and Tat(49-57) peptides.