Current Radiopharmaceuticals - Volume 2, Issue 4, 2009

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Positron Emission Tomography (PET) is a diagnostic imaging procedure used regularly to acquire essential clinical information. The PET-CT hybrid, which consists of two scanning machines: PET scanner and an x-ray Computed Tomography (CT). At present these represent the technological hierarchy of Nuclear Medicine, occupying an important position in diagnostics. In fact, PET-CT has the capability to evaluate diseases through a simultaneous functional and morphostructural analysis. This allows for an earlier diagnosis of the disease state which is crucial for obtaining the required information to provide a more reliable prognosis and therapy. Presently, the most frequently used PET radiotracer [18F]fluorodeoxyglucose (FDG) has a major role in oncology. Useful information is being regularly obtained by using both FDG and a selection of radiotracer compounds to evaluate some of the most important biological processes. Thus, creating an opening for ‘Molecular Imaging’ and providing a platform for a potential revolution in the clinical diagnostic field. In this review, we hope to present the most interesting technicalogical and methodological advances in clinical diagnostics for oncology, neurology, and cardiology. A particular attention is dedicated to the applications of PET in neuropsychiatric diseases and its connections with receptor imaging.

The labelling of small molecules with comparably bulky metal complexes under retention of their biological behaviour represents an incentive for inorganic and radiopharmaceutical chemistry. The availability of new 99mTc building blocks enabled new strategies with de novo designed derivatives of small, biologically or pharmaceutically relevant molecules. The scope of this report is to review recent developments in the field of small molecule labelling with 99mTc with a focus on design and synthesis. Although many new radio-bioconjugates of small molecules have been prepared recently, few have been tested in vivo. After a conceptual introduction describing strategies towards successful small molecule radiopharmaceuticals, selected examples from the classes of carbohydrates, vitamins and myocardial imaging agents will be presented. Since fundamental chemistry towards novel building blocks is essential for improving the armoury of radiopharmacy, developments with novel core complexes will be discussed. There are many reports of less common small biomolecules or pharmaceuticals labelled with 99mTc in the literature, this short review will conclude with some correspondingly selected examples.

Despite the success of 99mTc-sestamibi and 99mTc-tetrofosmin, the search for 99mTc heart imaging agents having a pharmacokinetic behavior much closer to that of an ideal perfusion tracer has been never interrupted. This short review illustrates advances in this field that have been made using the class of 99mTc complexes characterized by the presence of a terminal technetium-nitrogen multiple bond. This category of 99mTc compounds has proven to be particularly useful for cardiac imaging and a number of highly interesting compounds have been developed. The main chemical and biological properties of these agents are briefly summarized here.

The design of novel target-specific imaging agents based on 99mTc requires a considerable development of its coordination chemistry. Among all oxidation states available for technetium (-I to VII), the V oxidation state has been the most extensively studied in radiopharmaceutical chemistry, and the majority of the 99mTc-radiopharmaceuticals in clinical use contain the core [99mTc(O)]3+. More recently, the remarkable features of the organometallic precursor fac- [M(CO)3(H2O)3]+ (M = Re, Tc), introduced by Alberto et al., brought renewed interest in the design of innovative lowoxidation 99mTc-based radiopharmaceuticals. Owing to our interest on the design of innovative target-specific radioactive probes, we have been recently involved in the study of the chemistry of [M(O)]3+ and fac-[M(CO)3]+ (M = Re, Tc) with chelators combining a pyrazolyl unit with aliphatic amines and/or carboxylic acids or thioethers. Such research efforts are reviewed herein, where we present an overview of the chemistry, radiochemistry and biological properties of Re and 99mTc complexes anchored by those pyrazolyl-containing chelators with relevance in radiopharmaceutical research. The revised work focuses mainly on tricarbonyl M(I) complexes but M(V) oxocomplexes are also covered. This contribution intends to highlight the potential of pyrazolyl-containing chelators for the labeling of biologically active molecules with 99mTc(I), being presented a variety of examples which include peptides, peptide nucleic acids, inhibitors/substrates of enzymes and DNA-binders.

The development of a suitable radioligand for in vivo targeting CCK-2 receptor expressing tumours, such as medullary thyroid carcinoma, is a major recent focus in the field of radiopharmacy. Initial developments using [DGlu1]minigastrin (MG0) derivatives showed high uptake by the kidneys resulting as the dose limiting organ for radiopeptide therapy. In this study we describe the comparison of the optimised shortened peptide analogues, [DOTA0,DGlu1,desGlu2-6]minigastrin (DOTA-minigastrin-11) with [DOTA0,DGlu1,desGlu2-6,Ile11]minigastrin (DOTAilegastrin), labelled with 111In and 68Ga. In vitro tests included stability in plasma and plasma protein binding. Internalisation and receptor binding assays using a CCK-2 receptor positive cell-line (AR4-2J, rat pancreatic tumour cells) were performed and biodistribution in AR4-2J tumour bearing nude mice was studied. DOTA-ilegastrin showed a superior stability in plasma in comparison with DOTA-minigastrin-11. 68Ga/111In-labelled DOTA-ilegastrin revealed, however, significantly reduced internalisation and lower receptor affinity than DOTAminigastrin- 11. For both radiologiands rapid renal excretion and low unspecific retention in most organs was observed. Tumour uptake of 111In/68Ga-DOTA-minigastrin-11 was much higher (4.9 and 5.7 %ID/g 1 h p.i.) compared to 111In/68Ga- DOTA-ilegastrin (1.2 and 1.0 %ID/g). Kidney retention was clearly lower for the short chain analogues as compared to MG0 derivatives. Tumour uptake could be reduced by more than 60% by coinjection of 50 μg human minigastrin. DOTA-minigastrin-11 showed considerably lower kidney uptake, but also higher metabolic instability as compared to MG0 derivatives. No relevant differences between 111In- and 68Ga-labelled derivatives were observed. Replacement of methionine with isoleucine lead to dramatic loss of receptor affinity.