18F-labelled triazolyl-linked argininamides targeting the neuropeptide Y Y1R for PET Imaging of mammary carcinoma

NeuropeptideYY(1) receptors (Y1R) have been found to be overexpressed in a number of different tumours, such as breast, ovarian or renal cell cancer. In mammary carcinoma the highY(1)R density together with its high incidence of 85% in primary human breast cancers and 100% in breast cancer derived lymph node metastases attracted special attention. Therefore, the aim of this study was the development of radioligandsforY(1)R imaging by positron emission tomography (PET) with a special emphasis on imaging agents with reduced lipophilicity to provide a PET ligand with improved biodistribution in comparison with previously published tracers targeting theY(1)R. Three new radioligands based on BIBP3226, bearing an F-18-fluoroethoxy linker (12), an F-18-PEG-linker (13) or an F-18-fluoroglycosyl moiety (11) were radiosynthesised in high radioactivity yields. The new radioligands displayedY(1)R affinities of 2.8 nM (12), 29 nM (13) and 208 nM (11) and were characterised in vitro regarding binding to human breast cancer MCF-7-Y1 cells and slices of tumour xenografts. In vivo, small animal PET studies were conducted in nude mice bearing MCF-7-Y1 tumours. The binding to tumours, solid tumour slices and tumour cells correlated well with theY(1)R affinities. Although 12 and 13 showed displaceable and specific binding toY(1)R in vitro and in vivo, the radioligands still need to be optimised to achieve higher tumour-to-background ratios forY(1)R imaging by PET.Yet the present study is another step towards an optimized PET radioligand for imaging ofY(1)R in vivo

Perfusion Imaging with SPECT in the Era of Pathophysiology-Based Biomarkers for Alzheimer's Disease

SPECT allows registration of regional cerebral blood flow (rCBF) which is altered in a characteristic temporoparietal pattern in Alzheimer's Dementia. Numerous studies have shown the diagnostic value of reduced cerebral blood flow and metabolic changes using perfusion SPECT and FDG-PEPT in AD diagnosis as well as in differential diagnosis against frontotemporal dementia, dementia with Lewy bodies and vascular disease. Recently more pathophysiology-based biomarkers in CSF and Amyloid-PET tracers have been developed that probably have a higher diagnostic accuracy than the more indirect rCBF changes seen in perfusion SPECT. In the paper review, we describe recent advances in AD biomarkers as well as improvements in the SPECT technique

F-labeled glycoconjugate of PD156707 for imaging ET A receptor expression in thyroid carcinoma by positron emission tomography

Abstract: Disturbances of the endothelin axis have been described in tumor angiogenesis and in highly vascularized tumors, such as thyroid carcinoma. Consequently, the endothelin (ET) receptor offers a molecular target for the visualization of the endothelin system in vivo by positron emission tomography (PET). We therefore endeavoured to develop a subtype-selective ET A receptor (ET A R) radioligand by introduction of a glycosyl moiety as a hydrophilic building block into the lead compound PD156707. Employing click chemistry we synthesized the triazolyl conjugated fluoroglucosyl derivative 1 that had high selectivity for ET A R (4.5 nM) over ET B R (1.2 µM)

Cyclotrons Operated for Nuclear Medicine and Radiopharmacy in the German Speaking D-A-CH Countries: An Update on Current Status and Trends

Background: Cyclotrons form a central infrastructure and are a resource of medical radionuclides for the development of new radiotracers as well as the production and supply of clinically established radiopharmaceuticals for patient care in nuclear medicine. Aim: To provide an updated overview of the number and characteristics of cyclotrons that are currently in use within radiopharmaceutical sciences and for the development of radiopharmaceuticals to be used for patient care in Nuclear Medicine in Germany (D), Austria (A) and Switzerland (CH). Methods: Publicly available information on the cyclotron infrastructure was (i) consolidated and updated, (ii) supplemented by selective desktop research and, last but not least, (iii) validated by members of the committee of the academic “Working Group Radiochemistry and Radiopharmacy” (AGRR), consisting of radiochemists and radiopharmacists of the D-A-CH countries and belonging to the German Society of Nuclear Medicine (DGN), as well as the Radiopharmaceuticals Committee of the DGN. Results: In total, 42 cyclotrons were identified that are currently being operated for medical radionuclide production for imaging and therapy in Nuclear Medicine clinics, 32 of them in Germany, 4 in Austria and 6 in Switzerland. Two thirds of the cyclotrons reported (67%) are operated by universities, university hospitals or research institutions close to a university hospital, less by/in cooperation with industrial partners (29%) or a non-academic clinic/ PET-center (5%). Most of the cyclotrons (88%) are running with up to 18 MeV proton beams, which is sufficient for the production of the currently most common cyclotron-based radionuclides for PET imaging. Discussion: The data presented provide an academically-updated overview of the medical cyclotrons operated for the production of radiopharmaceuticals and their use in Nuclear Medicine in the D-A-CH countries. In this context, we discuss current developments and trends with a view to the cyclotron infrastructure in these countries, with a specific focus on organizational aspects

Detection of monoamine oxidase a in brain of living rats with [18F]fluoroethyl-harmol PET

Monoamine oxidase A (MAO-A) in brain, sympathetic fibres, and neuroendocrine tissues can catalyze the oxidative deamination of serotonin, noradrenaline and adrenaline, and contributes, along with MAO-B,to the catabolism of brain dopamine. As such, MAO-A is potentially an important target for molecular imaging, although the repertoire of suitable radiotracers is rather limited. The first successful MAO-A ligand for positron emission tomography (PET) studies of MAO-A was the b-carboline [11 C]harmine, which binds reversibly with nM affinity and high selectivity to the enzyme (Bergstrom et al., 1997). In contrast, the cerebral binding to MAO-A of [11C]clorgyline is difficult to quantify since the rate constant for irreversible binding is so very high, and due to the presence of a nonspecific binding component in white matter (Fowler et al., 2001). Other reversibly binding PET ligands for MAO-A include [11 C]befloxatone (Zanotti-Fregonara et al., 2013) and [11 C]befloxatone (Zanotti-Fregonara et al., 2013) and [11 CROMAO (Jensen et al., 2008). However, only [11 C]harmine is currently finding use in human PET studies of brain MAO-A (Chiuccariello et al., 2014). Logistic issues arising from the brief half-life of carbon-11 may be limiting the wider use of [11 C]harmine and other MAO-A ligands in research. Obtaining an MAO-A ligand labelled with fluorine-18 might afford multiple scans from a single radiosynthesis, and would make MAO-A scanning available to research centers lacking a medical cyclotron. In two preliminary reports, the b- carboline [18 F]fluoroethyl-harmol was found to have good properties for imaging in vivo, including high affinity and specificity, while corresponding PEGylated derivatives did not cross the blood-brain-barrier (Blom et al., 2008; Schieferstein et al., 2012). However, the specific binding of [18 F]fluoroethyl-harmol was not reported in detail in those reports. In this study, we report a high yield radiosynthesis of [18 F]fluoroethyl- harmol, and use small animal PET to map the distribution of its specific binding in brain of living rat