Technetium-99m based small molecule radiopharmaceuticals and radiotracers targeting inflammation and infection.

In nuclear medicine, the detection of inflamed and infected lesions is of growing interest. Extensive efforts have been made to develop radiopharmaceuticals specific for inflammation or for discriminating sterile inflammation from infection. 99mTc is the worldwide most widely used radioisotope for SPECT imaging. The scope of this review article is to give an overview on the development of 99mTc-labelled small molecule radiotracers targeting inflammatory lesions and infections, ranging from their radiopharmacological evaluation to examples of their clinical applications. A systematic overview of 99mTc-citrate, 99mTc-antibiotics and antifungal agents as well as 99mTc-labelled antimicrobial peptides is provided. Additionally, the class of 99mTc-labelled cyclooxygenase-2 inhibitors is discussed, since cyclooxygenases are known to play a key role in inflammatory diseases and also in malignant neoplastic diseases. In a short perspective, newer developments in the field of inflammation imaging covering 99mTc-labelled bacteriophages and chemotactic peptides are highlighted.

[11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats.

N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (SMe-ADAM, 1) is a highly potent and selective inhibitor of the serotonin transporter (SERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [(11)C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [(11)C]SMe-ADAM. The radiochemical yield was 27 +/- 5%, and the specific radioactivity was 26-40 GBq/micromol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SERT, such as the thalamus/hypothalamus region (3.59 +/- 0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74 +/- 0.95 at 60 min postinjection. The [(11)C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38 +/- 11% of the control value. Furthermore, no metabolites of [(11)C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [(11)C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

Synthesis and radiopharmacological evaluation of 2'-(4-fluorophenyl)-21-[18F]fluoro-20-oxo-11beta,17alpha-dihydroxy-pregn-4-eno[3,2-c]pyrazole as potential glucocorticoid receptor ligand for positron emission tomography (PET).

The radiosynthesis and the radiopharmacological evaluation of pyrazolo steroid 2'-(4-fluorophenyl)-21-[18F]fluoro-20-oxo-11beta,17alpha-dihydroxy-pregn-4-eno[3,2-c]pyrazole [18F]-2 is described. The radiolabeling was accomplished in 3-4% decay-corrected radiochemical yield within 80 min at an specific radioactivity of 0.8-1.2 Ci/micromol. Biodistribution studies in male Wistar rats showed an initial brain uptake of 0.25+/-0.03% ID/g after 5 min, which remained constant over 60 min. The radiopharmacological evaluation of compound [18F]-2 was completed with autoradiography using rat brain sections and micro-PET imaging.

Synthesis of 18F-labelled cyclooxygenase-2 (COX-2) inhibitors via Stille reaction with 4-[18F]fluoroiodobenzene as radiotracers for positron emission tomography (PET).

The Stille reaction with 4-[(18)F]fluoroiodobenzene as a novel approach for the synthesis of radiotracers for monitoring COX-2 expression by means of PET has been developed. Optimized reaction conditions were elaborated by screening of various catalyst systems and solvents. By using optimized reaction conditions (18)F-labelled COX-2 inhibitors [(18)F]-5 and [(18)F]-13 could be obtained in radiochemical yields of up to 94% and 68%, respectively, based upon 4-[(18)F]fluoroiodobenzene.

Synthesis of novel arylpyrazolo corticosteroids as potential ligands for imaging brain glucocorticoid receptors.

Corticosteroids regulate a variety of essential physiological functions, such as mineral balance and stress. The great interest in these steroids, especially the glucocorticoids, stems from roles they are thought to play in neuropsychiatric disorders, such as severe depression and anxiety.The development of glucocorticoid receptor (GR) ligands which are appropriately labeled with short-lived positron-emitting radioisotopes would allow the non-invasive in-vivo imaging and mapping of brain GRs by means of positron emission tomography (PET). In this context we have synthesized a series of novel arylpyrazolo steroids exhibiting different substitution patterns at the D-ring of the steroid skeleton, as ligands for brain GRs. Special attention was given to 4-fluorophenyl pyrazolo steroids, which are known to display high binding affinity toward the GR. The compounds were evaluated in a competitive radiometric receptor binding assay to determine their relative binding affinities (RBA) to the GR. Some compounds show good binding affinities of up to 56% in comparison to dexamethasone (100%). In initial experiments, selected candidates were labeled with the positron emitter fluorine-18 and in one case with the gamma-emitter iodine-131.

Synthesis and Binding Affinities of Novel Re-Containing 7alpha-Substituted Estradiol Complexes: Models for Breast Cancer Imaging Agents.

The diagnosis and staging of breast cancer could be improved by the development of imaging radiopharmaceuticals that provide a noninvasive determination of the estrogen receptor status in the tumor cells. Toward this goal, we have synthesized a number of novel Re-containing 7alpha-substituted estradiol complexes. The introduction of the 7alpha side chain involves the alkylation of tetrahydropyranyloxy-protected 6-keto estradiol. The methods used to introduce the rhenium metal involve "3 + 1" and "4 + 1" mixed ligand complexes (2a-c and 5, respectively), tricarbonyl dithioether complexes (3), and the cyclopentadienyltricarbonylmetal organometallic system (4ab, 6, 7). These complexes showed binding affinities for the estrogen receptor (as high as 45% for the "3 + 1" complex 2c) when compared to the native ligand estradiol. The polarity of some complexes (4ab) was modified to improve biodistribution properties by introducing (poly)ether linkages into the 7alpha side chain (6, 7). These complexes provide a further refinement of our understanding of ligand structure-binding affinity correlations for the estrogen receptor, and they furnish the synthetic groundwork for the synthesis of the analogous Tc-99m complexes for evaluation as breast tumor imaging agents.