Biological evaluation of a technetium-99m-labeled integrated tropane-BAT and its piperidine congener as potential dopamine transporter imaging agents.

Introduction: Recently, we have reported modification of (99m)Tc-TRODAT-1 by integrating the N2S2 metal chelating unit and the tropane skeleton. Results of a preliminary biodistribution study in rats were promising with respect to brain uptake. The present report deals with the further biological characterization of the (99m)Tc-labelled integrated TRODAT derivatives ((99m)Tc-TropaBAT and (99m)Tc-norchloro-TropaBAT) and with the synthesis and biological evaluation of a novel (99m)Tc-labelled piperidine-based derivative ((99m)Tc-PipBAT).

First preclinical evaluation of mono-[123I]iodohypericin as a necrosis-avid tracer agent.

Purpose: We have labelled hypericin, a polyphenolic polycyclic quinone found in St. John's wort (Hypericum perforatum), with( 123)I and evaluated mono-[(123)I]iodohypericin (MIH) as a potential necrosis-avid diagnostic tracer agent.

Methods: MIH was prepared by an electrophilic radioiodination method.

Non-invasive imaging of neuropathology in a rat model of alpha-synuclein overexpression.

Parkinson's disease is a neurodegenerative disorder affecting the dopaminergic neurons in the substantia nigra. Aggregation of alpha-synuclein appears to play a central role in the pathogenesis. Novel animal models for neurodegeneration have been generated by lentiviral vector-mediated locoregional overexpression of disease-associated genes in the adult brain.

Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial.

Background: The benefit of reperfusion therapies for ST-elevation acute myocardial infarction (STEMI) is limited by post-infarction left-ventricular (LV) dysfunction. Our aim was to investigate the effect of autologous bone marrow-derived stem cell (BMSC) transfer in the infarct-related artery on LV function and structure.

Methods: We did a randomised, double-blind, placebo-controlled study in 67 patients from whom we harvested bone marrow 1 day after successful percutaneous coronary intervention for STEMI.

Synthesis and biological evaluation of a technetium-99m(I)-tricarbonyl-labelled phenyltropane derivative.

A new tropane derivative was synthesized by combining a tridentate ligand, N-(2-picolylamine)-N-acetic acid (2-PAA), and a phenyltropane derivative. It was labelled with a [(99m)Tc(CO)(3)](+) moiety, resulting in the formation of two stable and neutral lipophilic isomers. Their identity was confirmed using radio-LC-MS.

Characterisation and biodistribution of two neutral 99mTc(CO)3 complexes with a tridentate ligand.

N-(2-Mercapto-propyl)-1,2-phenylenediamine (MPPDA) and N-beta-aminoethylglycine (AEG) were labelled with 99mTc(CO)3(+) to form the neutral complexes [99mTc(CO)3(MPPDA)] and [99mTc(CO)3(AEG)]. Both complexes were formed in excellent yields and their identity was confirmed by LC-MS. In mice, none of the new tracer agents showed brain uptake.

Development and biological evaluation of 99mTc-BAT-tropane esters.

Two (99m)Tc-BAT-tropane conjugates, i.e., technetium(V)-oxo-3-[N-(2-mercaptoethyl), N-(N'-(2-mercaptoethyl)-2-aminoethyl)]-aminopropyl 3beta-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.

Necrosis avid contrast agents: functional similarity versus structural diversity.

Two categories of necrosis-avid contrast agents (NACAs), namely porphyrin- and nonporphyrin-based complexes, have thus far been discovered as necrosis-targeting markers for noninvasive magnetic resonance imaging (MRI) identification of acute myocardial infarction, assessment of tissue or organ viability, and therapeutic evaluation after interventional therapies. In addition to necrosis labeling, other less-specific functions, such as first-pass perfusion, blood pool contrast effect, hepatobiliary contrast enhancement (CE), adrenal and spleen CE, and renal functional imaging, also are demonstrated with NACAs. Despite various investigations with a collection of clues in favor of certain hypotheses, the mechanisms of such a unique targetability for NACAs still remain to be elucidated.

Regional brain activation during proximal stomach distention in humans: A positron emission tomography study.

Background & Aims: Hypersensitivity to proximal gastric distention due to abnormal central nervous system processing of visceral stimuli has been suggested as a possible underlying pathophysiologic mechanism in functional dyspepsia. However, the cortical regions activated by distention of the proximal stomach have not been identified. The aim of this study was to investigate regional brain activation during painful and nonpainful proximal gastric distention in humans.

Optimization of geometrical calibration in pinhole SPECT.

Previously, we developed a method to determine the acquisition geometry of a pinhole camera. This information is needed for the correct reconstruction of pinhole single photon emission computed tomography images. The method uses a calibration phantom consisting of three point sources and their positions in the field of view (FOV) influence the accuracy of the geometry estimate.

Technetium-99m labelled integrated tropane-BAT as a potential dopamine transporter tracer.

To reduce the molecular weight of 99mTc-labelled tropanes with the aim to enhance the passage over the blood-brain barrier, a so-called integrated tropane-BAT construct was developed. For this purpose a mercaptoethyl substituent was attached to the amine nitrogen atom of a nortropane precursor and the methyl carboxylate in 2beta-position was converted to a 2-mercaptoethylaminomethylene substituent. This integrated tropane-BAT construct could be labelled efficiently (85-90%) with technetium-99m.

Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry.

This study aimed to evaluate tumour hypoxia by comparing [(18)F]Fluoromisonidazole uptake measured using positron emission tomography ([(18)F]FMISO-PET) with immunohistochemical (IHC) staining techniques. Syngeneic rhabdomyosarcoma (R1) tumour pieces were transplanted subcutaneously in the flanks of WAG/Rij rats. Tumours were analysed at volumes between 0.

Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: sensitivity, inter-observer variability and prognostic value.

Purpose: 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) PET imaging studies allow the investigation of metabolism and amino acid transport in brain tumours. Their (relative) usefulness and prognostic value in suspected recurrence or progression of primary brain tumours after previous therapy is an issue of debate. The aim of this study was to compare directly both radioligands in this setting.

In vitro evaluation and biodistribution of a 99mTc-labeled anti-VEGF peptide targeting neuropilin-1.

Neuropilins (NRP) are receptors of angiogenic vascular endothelial growth factor (VEGF). Their overexpression was correlated with tumor angiogenesis and growth suggesting that their specific targeting could provide a new marker of tumor progression. Here, we observed in vitro that new (99m)Tc-labeled derivative of anti-VEGF heptapeptide, ATWLPPR, binds to NRP1 but not to NRP2.

Dopamine transporter SPECT using fast kinetic ligands: 123I-FP-beta-CIT versus 99mTc-TRODAT-1.

A comparative study was carried out on two promising presynaptic dopamine transporter single-photon emission tomography (SPECT) radioligands with a fast pharmacokinetic profile, 123I-FP-beta-CIT (FP) and 99mTc-TRODAT-1 (TR), in order to assess their differential diagnostic power in early parkinsonism and their sensitivity for detection of disease progression. This cross-sectional study was conducted on 96 patients with early-stage parkinsonism referred in a tertiary clinical setting. Mean disease duration was 2.

Accumulation and photocytotoxicity of hypericin and analogs in two- and three-dimensional cultures of transitional cell carcinoma cells.

The aim of this study was to investigate the in vitro cellular accumulation, distribution and photocytotoxic effect of hypericin in two-dimensional (2-D) and three-dimensional (3-D) cultured RT-112 transitional cell carcinoma cells of the bladder. In addition, two iodinated derivatives of hypericin were incorporated to investigate whether these analogs, with their increased lipophilicity and heavy-atom effect, display a different biological behavior and optimized photodynamic effect. The results indicate that hypericin and mono-iodohypericin behave similarly in terms of cellular accumulation, spheroidal distribution and photocytotoxic effect.

Synthesis of 18F-fluoroalkyl-beta-D-glucosides and their evaluation as tracers for sodium-dependent glucose transporters.

Unlabelled: Three omega-(18)F-fluoro-n-alkyl-beta-D-glucosides (alkyl = ethyl (5a)), n-butyl (5b), and n-octyl (5c)) were synthesized and evaluated as potential substrates for the sodium/D-glucose cotransporter SGLT1.

Methods: The ligands were prepared by (18)F-fluoride displacement of the corresponding tetraacetyl-protected tosylate alkylglucoside precursors in CH(3)CN, followed by hydrolysis of the protective acetate esters with NaOMe/MeOH. Transport of the nonradioactive analogs 5a, 5b, and 5c by the human sodium-D-glucose cotransporter hSGLT1 was characterized in vitro in oocytes of Xenopus laevis that expressed hSGLT1.

Image-derived input function for [11C]flumazenil kinetic analysis in human brain.

Purpose: We describe a method for analysis of [11C]flumazenil data using an input curve directly derived from the positron emission tomography (PET) images.

Procedure: The shape of the tracer plasma curve was obtained from the product of the intact flumazenil fraction in plasma in six arterial samples and the internal carotid artery time-activity curve (TAC). The resulting curve was calibrated using the [11C]flumazenil concentration in three of the six samples.

An efficient HPLC method for the analysis of isomeric purity of technetium-99m-exametazime and identity confirmation using LC-MS.

99mTc-exametazime (99mTc-d,l-HMPAO, 99mTc-d,l-hexamethylpropyleneamine oxime) is a neutral rather unstable complex of short-lived 99mTc (t(1/2)=6 h) with the d,l-isomer (mixture of D,D- and L,L-isomers) of a bis-amine bis-oxime tetraligand. It is widely used for measurement of regional cerebral perfusion in nuclear medicine. The meso-isomer (D,L-form) should not be present in a preparation as it is not retained in brain and thus does not provide clinically useful information.

Identity confirmation of 99mTc-MAG3, 99mTc-sestamibi and 99mTc-ECD using radio-LC-MS.

Due to the low concentrations in which 99mTc-radiopharmaceuticals are obtained (4-40 ng/ml), confirmation of the identity of these tracer agents in the European Pharmacopoeia is generally performed only indirectly by assessment of their retention times on RP-HPLC. We have investigated whether it is possible to obtain more direct proof of the identity of technetium-99m labelled radiopharmaceuticals using radio-LC-MS. As representative examples, negatively charged 99mTc-MAG3, positively charged 99mTc-Sestamibi and neutral 99mTc-ECD were used.

RP-HPLC separation of the diastereomers of technetium-99m labelled tropanes and identity confirmation using radio-LC-MS.

99mTc-TRODAT-1 (technetium(V)-oxo-2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]]amino]-ethanethiolato(3-)) and 99mTc-TRODAT-M, the 4-methylphenyl derivative of 99mTc-TRODAT-1, are at this moment being evaluated in clinical trials as imaging agents for the central nervous dopamine transporter system.

Characterization of pinhole SPECT acquisition geometry.

A method is presented to estimate the acquisition geometry of a pinhole single photon emission computed tomography (SPECT) camera with a circular detector orbit. This information is needed for the reconstruction of tomographic images. The calibration uses the point source projection locations of a tomographic acquisition of three point sources located at known distances from each other.

Synthesis and biologic evaluation of (11)c-methyl-d-glucoside, a tracer of the sodium-dependent glucose transporters.

Unlabelled: This study aimed to synthesize and to evaluate the biologic characteristics of (11)C labeled methyl-D-glucoside, a nonmetabolizable tracer that is selectively transported by sodium-dependent glucose transporters (SGLTs).

Methods: (11)C-Methyl-D-glucoside was prepared by methylation of glucose with (11)C-methyl triflate and was obtained as a mixture of anomers that were separated with high-performance liquid chromatography. The biodistribution of both the D- and L-isomers was determined in mice, and the presence of metabolites in the blood was investigated.

Prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose chemotherapy and stem cell transplantation.

The study assessed the prognostic value of fluorine 18-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) after salvage chemotherapy before high-dose chemotherapy with stem cell transplantation (HDT/SCT) in patients with induction failure or relapsing chemosensitive lymphoma. Retrospective analysis of the clinical and conventional imaging data of 60 patients scheduled for HDT/SCT was performed in parallel with the analysis of the [18F]FDG-PET results. To determine the ability of [18F]FDG-PET to predict clinical outcome, PET images were reread without knowledge of conventional imaging and clinical history.