Current Topics in Medicinal Chemistry - Volume 12, Issue 23, 2012

Alpha-particles are of considerable growing interest for Targeted Alpha Therapy (TAT). TAT gains more attention as new targets, chemical labeling techniques and α-particle emitters are developed but translation of TAT into the clinic has been slow, in part because of the limited availability and the short physical half-lives of some of the available α- particle emitters. This article is an up-to-date overview of the literature concerning α-emitters used for TAT of cancer. It briefly describes the nuclear characteristics, the production parameters (targets, extraction and purification), the complexation properties of these radionuclides to chelates and biological vectors and finally draws-upon the preclinical and clinical studies that have been performed over the past two decades. Radiobiology and dosimetry aspects are also presented in this paper.

The successful application of OctreoScan® ([111In-DTPA]octreotide) in the diagnosis of sst2-expressing neuroendocrine tumors (NETs), on one hand, and the manifestation of peptide receptor targets in a wide range of human cancers, on the other, have synergistically induced a booming emergence of numerous radiolabeled peptide (radiopeptide) probes for tumor diagnosis and therapy in man. Definition of molecular targets and their relation to neoplastic disease has preceded peptide-based radiopharmaceutical design and development. New criteria have been set to safeguard efficient localization of radionuclides on tumor-associated high affinity – low capacity peptide receptor systems. New technical and biological terms, such as specific activity or receptor affinity and internalization, have invaded the Radiopharmacy domain and have irrevocably altered our concept of radiopharmaceutical design. Nonetheless, 99mTc remains the gold standard of diagnostic nuclear medicine as a result of ideal nuclear characteristics, cost-effectiveness and wide availability in high purity and high specific activity by means of commercial 99Mo/99mTc-generators. The evolution of conventional 99mTc-perfusion agents into modern state-of-the-art molecular radiopharmaceuticals has been a challenge addressed by several researchers. The present review summarizes recent advances in the development of 99mTc-labeled peptides for in vivo targeting of neoplastic disease, and, in particular, those functionalized with acyclic tetraamines. Conclusions on their applicability in non-invasive diagnosis and staging of cancer patients are drawn.

For iodination (125/127I) 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. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of 125/127I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no 127I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification.

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. Therefore we suggest a set of standardized requirements to quantify RCP by HPLC for radiolabelled DTPA- or DOTA-peptides. Moreover, a dosimetry model was developed to calculate the doses in the reaction vials during radiolabelling and storage of the radiopeptides, and to predict RCP in the presence and absence of quenchers. RCP was measured by HPLC, and a relation between radiation dose and radiolysis of RCP was established. The here described quenchers are tested individually as ƒ(concentration) to investigate efficacy to reduce radiolysis of radiolabelled methionine-containing regulatory peptides.

The paper focuses on the β-emitting radionuclides which might be useful for peptide receptor radionuclide therapy, PRRT. For the effective design of the radiopharmaceutical, the choice of radionuclide will depend on the purpose for which the radioligand is being used and on the physicochemical properties of the radionuclide. The important factor is also the availability and the cost of production. The physical characteristics of several radionuclides which are currently used or can be considered as potential candidates for PRRT is provided, followed by short description of production methods and chemical aspects of their use in preparation of peptide-based radiopharmaceuticals. Somatostatin analogues labeled with radionuclides have been a successful example of PRRT. For treatment of patients with inoperable or metastasized neuroendocrine tumors, somatostatin analogues labeled with the radioisotopes 111In, 90Y and 177Lu have been used so far. Labeling with 111In, mainly an Auger electron emitter, resulted in no reduction of tumor size while somatostatin analogues labeled with 90Y and 177Lu gave overall positive response and improved the patients’ quality of life. These promising results together with the increasing availability of other β-emitting radionuclides are a good basis for further studies.

Dual-modality contrast agents, such as radiolabeled nanoparticles, are promising candidates for a number of diagnostic applications, since they combine the advantages of two different imaging modalities, namely SPECT or PET imaging with MR imaging. The benefit of such a combination is to more accurately interpret disease and abnormalities in vivo, by exploiting the advantages of each imaging technique, i.e. high sensitivity for SPECT/PET, high resolution anatomical information for MRI. In this review article, we provide an overview of recent findings in the synthesis, evaluation and application of radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI imaging probes.