Cyclotron production of high–specific activity 55Co and in vivo evaluation of the stability of 55Co metal-chelate-peptide complexes

This work describes the production of high–specific activity 55 Co and the evaluation of the stability of 55 Co-metal-chelate-peptide complexes in vivo. 55 Co was produced via the 58 Ni(p,α) 55 Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96 GBq/μmol. 55 Co-DO3A and 55 Co-NO2A peptide complexes were radiolabeled at 3.7 MBq/μg and injected into HCT-116 tumor xenografted mice. Positron emission tomography (PET) and biodistribution studies were performed at 24 and 48 hours postinjection and compared to those of 55 CoCl 2 . Both 55 Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers’ uptake in the liver by sixfold at 24 hours with ˜ 1% ID/g and at 48 hours with ˜ 0.5% ID/g and reducing uptake in the heart by fourfold at 24 hours with ˜ 0.7% ID/g and sevenfold at 48 hours with ˜ 0.35% ID/g. These results support the use of 55 Co as a promising new radiotracer for PET imaging of cancer and other diseases

Aptamer-based therapeutics and their potential in radiopharmaceutical design

Aptamers, short, single stranded oligonucleotide entities, have been developed in the past 15 years against a plethora of targets and for a variety of applications. These range from inhibition of receptors and enzymes to the identification of small molecules in sensor applications, and from the development of targeted therapeutic to the design of novel diagnostic and imaging agents. Furthermore, aptamers have been designed for targets that cover a wide range of diseases, from HIV to tropical diseases, cancer and inflammation. Their easy development and flexibility of use and manipulation, offers further potential. In this paper we review their selection and consider some of the recent applications of aptamers in the design of radiopharmaceuticals for the targeted radiotherapy and medical imaging of disease

In Vivo Radionuclide Generators for Diagnostics and Therapy

In vivo radionuclide generators make complex combinations of physical and chemical properties available for medical diagnostics and therapy. Perhaps the best-known in vivo generator is 212Pb/212Bi, which takes advantage of the extended half-life of 212Pb to execute a targeted delivery of the therapeutic short-lived α-emitter 212Bi. Often, as in the case of 81Rb/81Kr, chemical changes resulting from the transmutation of the parent are relied upon for diagnostic value. In other instances such as with extended alpha decay chains, chemical changes may lead to unwanted consequences. This article reviews some common and not-so-common in vivo generators with the purpose of understanding their value in medicine and medical research. This is currently relevant in light of a recent push for alpha emitters in targeted therapies, which often come with extended decay chains

Modular Strategies for PET Imaging Agents

In recent years, modular and simplified chemical and biological strategies have been developed for the synthesis and implementation of positron emission tomography (PET) radiotracers. New developments in bioconjugation and synthetic methodologies, in combination with advances in macromolecular delivery systems and gene-expression imaging, reflect a need to reduce radiosynthesis burden in order to accelerate imaging agent development. These new approaches, which are often mindful of existing infrastructure and available resources, are anticipated to provide a more approachable entry point for researchers interested in using PET to translate in vitro research to in vivo imaging.Chemistry and Chemical Biolog

The Foundations of the Development of Technologies of the Synthesis of Radiopharmaceuticals

The selection of precursors (for example chelating agents) and development of a technique of chemical modification of the target molecules retaining its ability to bind to specific receptors are very important in the synthesis of radiopharmaceuticals. As some important precursors for target radiopharmaceuticals omega-iodo-aliphatic carboxylic acids and their esters can be used. We have developed an environmentally safe process for producing omega-iodoaliphatic carboxylic acids and their esters of the available, inexpensive and low toxic aliphatic cyclic ketones. We proposed a new method for the synthesis of the chelating agents omega-thia- or (bis(2-hydroxyethyl)amino)- aliphatic carboxylic acids (chelate 1 and chelate 2), which was caused by the existing disadvantages in the existing methods. Thus, based on our method the precursors (chelates) with yield of over 70-90% on the final stage were synthesized, and then the high effectiveness in producing target radiopharmaceuticals using different biomolecules was showed. 99mTc-chelates complexes were prepared with radiochemical purity >91% and found to be stable at room temperature for six hours

Gallium-68: Radiolabeling of Radiopharmaceuticals for PET Imaging - A Lot to Consider

Gallium-68 was applied for positron emission tomography (PET) imaging already in the early beginnings of PET imaging. Today, with the introduction of PSMA-targeting tracers (e.g. PSMA-11, PSMA-617, and PSMA-I&T), the number of clinical applications of 68Ga-radiopharmaceuticals for diagnostic imaging has grown considerably. This development was initiated and supported already in the mid-2000s by the commercial availability of 68Ge/68Ga generators designed for clinical usage. This progression was accompanied by the development of several purification methods to generator eluate as well as sophisticated 68Ga-radiopharmaceuticals. Due to the 68Ga-rush, the need for implementation of gallium-68 (depending on production route) and its certain tracers into the pharmacopeia increased. Based on the specifications given by the pharmacopeia, interest focused on the development of automated synthesis systems, 99mTc-analog kits with regard to patient as well as operator safety

Peptide-chelating agent conjugate for selective targeting of somatostatin receptor type1: Synthesis and characterization

Previously reported results suggest that the analogue of the somatostatin des-AA 1,2,5[D-Trp 8,IAmp 9]-somatostatin (CH-275) peptide bearing chelating agents able to coordinate radioactive metals could be used for scintigraphic imaging of tumor lesions overexpressing sstr1. An efficient synthetic procedure for the preparation of the somatostatin analogue CH-275 and its conjugate DTPAGlu-Gly-CH-275, bearing the chelating agent DTPAGlu (DTPAGlu = N,N-bis[2-[bis(carboxy-ethyl)amino]ethyl]-L-glutamic acid) on the N-terminus, by solid-phase peptide synthesis and 9-flourenymethyoxycarbonyl (Fmoc) chemistry, is here reported. Rapid and efficient labeling of DTPAGlu-Gly-CH-275 was achieved by addition of IIIIn(III) to the compound. Typical yields were greater than 97% as determined by reversed phase high performance liquid chromatography (HPLC) at specific activities in the range 4-9 GBq/μmol (100-250 Ci/mmol). A preliminary biological assay of the binding ability of IIIIn-DTPAGlu-Gly-CH-275 indicates, however, that the labeled compound does not display any specific interaction with somatostatin sstrl receptors in the tested cell lines. To confirm this unexpected negative result, competition binding experiments were carried out, in which fixed tracer amounts of the 125!-labeled somatostatin-14 were incubated with the receptor-expressing cells in the presence of DTPAGlu-Gly-CH-275 or CH-275 at concentrations ranging from 10 -10 to 10 -3 M. While CH-275 shows a IC 50 of 80 nM similar to that already found in displacement experiments on CHO-Kl sstrl-transfected cells, DTPAGlu-Gly-CH-275 displays instead very low or negligible affinity towards this receptor. The NMR solution characterization indicates that the presence of DTPAGlu does not influence the conformational and chemical features of the peptide moiety, thus suggesting that the loss in binding activity should be due to steric hindrance of either the chelating agent DTPAGlu or its indium comple

Radiolabeling of Theranostic Nanosystems

In the recent years, progress in nanotechnology has significantly contributed to the development of novel pharmaceutical formulations to overcome the drawbacks of conventional treatments and improve the therapeutic outcome in many diseases, especially cancer. Nanoparticle vectors have demonstrated the potential to concomitantly deliver diagnostic and therapeutic payloads to diseased tissue. Due to their special physical and chemical properties, the characteristics and function of nanoparticles are tunable based on biological molecular targets and specific desired features (e.g., surface chemistry and diagnostic radioisotope labeling). Within the past decade, several theranostic nanoparticles have been developed as a multifunctional nanosystems which combine the diagnostic and therapeutic functionalities into a single drug delivery platform. Theranostic nanosystems can provide useful information on a real-time systemic distribution of the developed nanosystem and simultaneously transport the therapeutic payload. In general, the diagnostic functionality of theranostic nanoparticles can be achieved through labeling gamma-emitted radioactive isotopes on the surface of nanoparticles which facilitates noninvasive detection using nuclear molecular imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), meanwhile, the therapeutic effect arises from the potent drug released from the nanoparticle. Moreover, some radioisotopes can concurrently emit both gamma radiation and high-energy particles (e.g., alpha, beta, and Auger electrons), prompting the use either alone for radiotheranostics or synergistically with chemotherapy. This chapter provides an overview of the fundamentals of radiochemistry and relevant radiolabeling strategies for theranostic nanosystem development as well as the methods for the preclinical evaluation of radiolabeled nanoparticles. Furthermore, preclinical case studies of recently developed theranostic nanosystems will be highlighted.Peer reviewe