Heinrich Hubert Coenen

Labeling of benzodioxin piperazines with fluorine-18 as prospective radioligands for selective imaging of dopamine D4 receptors.

The D(4) receptor is of high interest for research and clinical application but puts high demands on appropriate radioligands to be useful tools for investigation. Search for adequate radioligands suitable for in vivo imaging is therefore still in progress. The potential neuroleptic drug 6-(4-[4-fluorobenzyl]piperazin-1-yl)benzodioxin shows high affinity and selectivity to the D(4) receptor. Derivatization of this lead structure by adding hydrophilic moieties was carried out in order to lower its lipophilicity what led to three new putative dopamine receptor D(4) ligands. A comprehensive description of the syntheses of standard compounds and corresponding labeling precursors is given which were obtained in satisfactory yields. Furthermore, the radiosyntheses by direct (18) F-labeling and build-up synthesis were compared. All derivatives of 6-(4-[4-fluorobenzyl]-piperazin-1-yl)benzodioxin were successfully synthesized in (18) F-labeled form with radiochemical yields of 9-35% and molar activities of 30-60 GBq/µmol using one-pot procedures.

Production of no-carrier-added radiobromine: new nickel selenide target and optimized separation by dry distillation

Abstract Nickel(II) selenide (NiSe) was investigated as a new high-current target material for cyclotron production of radiobromine, as it contains a higher amount of selenium and has a lower melting point than the widely used Cu2Se. Using a slanted target system, NiSe was successfully tested up to beam currents of 16 μA so far. With regard to the isolation of no-carrier-added (n.c.a.) radiobromide from the target material, an improved dry distillation device with high yields of 76% – 86% was developed. The implementation of a special custom-made quartz funnel decreased the dead volume of the apparatus and a quartz capillary for trapping the radiobromine allowed to concentrate the radioactivity in a small volume of less than 100 μL of 0.1 M NaOH, ready for immediate subsequent radiosyntheses. Thus, the new apparatus improves the handling of the isolation procedure and the radioactive product. The radiochemical purity of the resulting solution of n.c.a. [*Br]bromide was verified by radio-IC where no other species were detected.

Positron and γ-ray intensities in the decay of 45Ti

Abstract To evaluate the PET-imaging properties of the promising positron emitter 45Ti, its β+- and γ-ray intensities were measured. Use of the cation-exchange resin DOWEX 50W×8 (H+-form) enabled the isolation of radiochemically pure, no-carrier-added 45Ti from “bulk” scandium after proton bombardment. Thin, no-carrier-added 45Ti samples were prepared. The combination of γ-ray and X-ray spectrometry with γγ-coincidence counting allowed for the first time the experimental determination of the positron intensity as (85.67 ± 2.23)% and the absolute intensity of the 720.22 keV γ-ray as (0.1171 ± 0.0057)%.

Towards authentically labelled bi-modal PET(SPECT)/MR-probes

Application of radiolabelled, existing MRI probes using a suitable reporter group for multimodal PET(SPECT)/MRI imaging is limited due to the required alteration of the molecular structure and thus changing their in vivo properties. Radiolabelling of existing MRI contrast agents with PET(SPECT) isotopes of paramagnetic elements offers a simple way to address this issue. Therefore, new routes to the production of SPECT/PET-radionuclides 147,149Gd and 52gMn were examined which can be applied for n.c.a. labelling of Gd(III) and Mn(II) MRI contrast agents. Additionally, Mn(II)-based complexes stable for in vivo application are to be synthesized. Reaction cross sections and experimental thick target yields were measured by irradiation of natCr or Eu2O3. Integral yields were calculated from measured excitation functions. A radiochemical separation of Mn from Cr was developed based on cation-exchange chromatography [1]. Cross section data of the natEu(d,x) and natEu(p,x) reactions were measured up to 70.9 MeV and 44.8 MeV, respectively. Integral yields of up to 177.3 MBq/μAh and 81.6 MBq/μAh for natEu(d,x)147,149Gd reactions and up to 43.3 MBq/μAh and 61.8 MBq/μAh for natEu(p,x)147,149Gd reactions, respectively, were calculated. Those were several times higher than for α- or 3He induced reactions on highly enriched 144Sm [2, 3]. With n.c.a. 52Mn, also cross sections of co-produced 48V, 48,49,51Cr, 52gMn were determined in the energy range of 7.6 to 45 MeV. The production rates of 52g,mMn were measured from 8.2 to 16.9 MeV with up to 13.1 MBq/μAh which was separated from natCr by column chromatography. Production data of the SPECT nuclides 147,149Gd and the PET nuclide 52gMn were established. Different to Mn a practical isolation procedure for Gd is still required. Current work focuses on the radiolabelling of stable complexes of manganese (II) with the goal to develop PET/MRI tracers addressing molecular targets.

New potent A1 adenosine receptor radioligands for positron emission tomography.

8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is meanwhile an accepted receptor ligand to examine the A1 adenosine receptor (A1AR) in humans by positron emission tomography (PET). A major drawback of this compound is its rather fast metabolic degradation in vivo. Therefore two new xanthine derivatives, namely 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (CBCPM; 5) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (CPMMCB; 6) were designed and synthesized as potential alternatives to CPFPX. In membrane binding studies both compounds showed nanomolar affinity for the A1AR. In vitro autoradiographic studies of [18F]5 and [18F]6, using rat brain slices, showed the expected accumulation in regions known to have a high adenosine A1 receptor expression while exhibiting the necessary low unspecific binding. However, in vitro metabolite studies using human liver microsomes revealed a comparable metabolic degradation rate for both new xanthine derivatives and CPFPX.

Adapting MR-BrainPET scans for comparison with conventional PET: experiences with dynamic FET-PET in brain tumours

Imaging results from subsequent measurements (preclinical 3T MR-BrainPET, HR+) are compared. O-(2-[18F]fluoroethyl)-L-tyrosine (FET) may exhibit non-uniform tracer uptake in gliomas. The aim was to analyse and adapt the physical properties of the scanners and study variations of biological tumour volume (BTV) in early and late FET-PET. Spatial resolution of the BrainPET and HR+ was measured according to NEMA standard. For evaluation of a threshold-based volume determination -as used for BTV- volumes of an 18F-filled spheres phantom were evaluated. Influence of different filter kernels for correction of differences in spatial resolution hereon was compared. Differences in BTV between early and late FET-PET of 45 patients were analysed. BTV was determined using a tumour-to-brain ratio ≥1.6 [1]. Spatial resolution (FWHM) of the BrainPET was 2.63mm–3.47mm and 4.39mm–5.10mm for the HR+ (10mm off-centre) [2]. 3D-filtered backprojection was used for reconstruction [3]. BTV of largest sphere was 22.8ml in HR+ and between 23.2ml (unfiltered) and 24.5ml (3D-Gaussian 3.5mm) in the BrainPET. BTV of smallest sphere was 0.1 ml in HR+ and between 0.2ml (unfiltered) and 0.06ml (3D-Gaussian 3.5mm) in the BrainPET. A 2.5mm filter showed the smallest deviation for all spheres and was applied to the BrainPET data for cross-scanner comparison. Changes in BTV >10% were considered significant and not related to physical differences between scanners. 41% of patients showed a considerable deviation between early and late FET-PET. BTV increased in 14 patients. Four patients showed a FET positive region only in late FET-PET. Taking into account the physical differences of PET scanners is important for cross-scanner studies. It was shown in a patient study that BTV may vary between early and late FET-PET, which is important for patient management and needs further investigation. Figure 1 MRI and FET-PET scan of a patient with oligodendroglioma WHO grade II. T1-weighted MR image (MPRAGE) acquired simultaneously to the early PET scan with the 3T MR-BrainPET (top). Summation scan 20-40 min post-injection (BrainPET, middle), summation scan ...

Synthesis and preliminary pharmacological evaluation of a new putative radioiodinated AMPA receptor ligand for molecular imaging

Summary A new (radio)iodinated AMPA receptor ligand has been developed and pharmacologically evaluated in vitro and ex vivo using rodents. The new radioligand was directly labeled by electrophilic radioiodo-destannylation with iodine- 131 in high radiochemical yields of 97% within 2 min. The new radioligand showed an excellent initial brain uptake of 2.1%ID/g at 10 min post injection, but a fast wash-out reduced the uptake by about 10-fold at 60 min post injection. Due to high nonspecific binding accompanied with a uniform distribution in brain tissue, however, the new radiotracer appears not suitable for AMPA receptor imaging in vivo.