Bent W. Schoultz

Potential in vivo generator for alpha-particle therapy with 212Bi: Presentation of a system to minimize escape of daughter nuclide after decay of 212Pb to 212Bi

Abstract Radiopharmaceuticals based on 212Pb (t1/2=10.6 h) are of interest for use as an in vivo generator of α-particle emitting 212Bi (t1/2=60.6 min). Sterically stabilized liposomes were evaluated as carriers of 212Pb/212Bi radionuclides in the reported study. 212Pb/212Bi-containing vesicles were prepared by ionophore mediated loading of 212Pb into preformed liposomes. The liposomal uptake of 212Pb with or without various concentrations of lead carrier was investigated. The retention of 212Pb and 212Bi in liposomes incubated in serum was studied. Conditions were found yielding a high and rapid uptake of 212Pb in liposomes. 90±2% of 212Pb was incorporated after 30 min. The retention of radionuclides was high, 95% of 212Pb and 212Bi were retained in liposomes after incubating for 20 h at 37°C in serum. The results from the present work indicate that an effective retention of 212Bi after the β--decay of 212Pb is achievable. This technology could be the basis of α-emitting radiopharmaceuticals built upon 212Pb.

Synthesis and evaluation of a full-agonist orvinol for PET-imaging of opioid receptors: [11C]PEO.

Antagonist radiotracers have shown only a low sensitivity for detecting competition from high-efficacy agonists at opioid receptors (ORs) in vivo. We report that [(11)C]PEO binds with high affinity to mu and kappa-opioid receptors, is a full agonist, and concentrates in brain regions of rats with a high density of the mu-OR after intravenous injection. Blocking studies with mu and kappa-OR selective compounds demonstrated that the binding of [(11)C]PEO is saturable and selective to the mu-OR in rat brain.

A Fully Automated Radiosynthesis of [18F]Fluoroethyl-Diprenorphine on a Single Module by Use of SPE Cartridges for Preparation of High Quality 2-[18F]Fluoroethyl Tosylate

We have developed a new method for automated production of 2-[18F]fluoroethyl tosylate ([18F]FETos) that enables 18F-alkylation to provide PET tracers with high chemical purity. The method is based on the removal of excess ethylene glycol bistosylate precursor by precipitation and subsequent filtration and purification of the filtrate by means of solid phase extraction cartridges (SPE). The method is integrated to a single synthesis module and thereby provides the advantage over previous methods of not requiring HPLC purification, as demonstrated by the full radiosynthesis of the potent opioid receptor PET tracer [18F]fluoroethyldiprenorphine.

Spinal long-term potentiation is associated with reduced opioid neurotransmission in the rat brain.

Introduction:  Neuronal events leading to development of long‐term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying hyperalgesia. In the present study, we examine if induction of spinal LTP may be associated with functional changes in the supraspinal opioidergic system. The opioid receptors (ORs) play a key role in nociceptive processing and controlling the descending modulatory system to the spinal cord.

Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide

2-[18F]Fluoroethyl azide ([18F]FEA) can readily be obtained by nucleophilic substitution of 2-azidoethyl-4-toluenesulfonate with [18F]fluoride (half-life 110 min), and has become widely used as a reagent for ‘click’ labeling of PET tracers. However, distillation of [18F]FEA is typically required, which is time-consuming and unpractical for routine applications. In addition, copper(I)-catalyzed cycloaddition of [18F]FEA with non-activated alkynes, and with substrates containing labile functional groups, can be challenging. Herein, we report a highly efficient and practical ligand-accelerated one-pot/two-step method for ‘click’ labeling of small molecule tracers with [18F]FEA. The method exploits the ability of the copper(I) ligand bathophenanthrolinedisulfonate to accelerate the rate of the cycloaddition reaction. As a result, alkynes can be added directly to the crude reaction mixture containing [18F]FEA, and as cyclisation occurs almost immediately at room temperature, the reaction is tolerant to labile functional groups. The method was demonstrated by reacting [18F]FEA with a series of alkyne-functionalized 6-halopurines to give the corresponding triazoles in 55–76% analytical radiochemical yield.

Synthesis and Evaluation of Three Structurally Related 18F-Labeled Orvinols of Different Intrinsic Activities: 6-O-[18F]Fluoroethyl-diprenorphine ([18F]FDPN), 6-O-[18F]Fluoroethyl-buprenorphine ([18F]FBPN), and 6-O-[18F]Fluoroethyl-phenethyl-orvinol ([18F]FPEO)

We report the synthesis and biological evaluation of a triplet of 6-O-(18)F-fluoroethylated derivatives of structurally related orvinols that span across the full range of intrinsic activities, the antagonist diprenorphine, the partial agonist buprenorphine, and the full agonist phenethyl-orvinol. [(18)F]fluoroethyl-diprenorphine, [(18)F]fluoroethyl-buprenorphine, and [(18)F]fluoroethyl-phenethyl-orvinol were prepared in high yields and quality from their 6-O-desmethyl-precursors. The results indicate suitable properties of the three 6-O-(18)F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties.

Positron emission tomography and pharmacokinetics of 2-[18F]-fluoroethyl choline for metabolic studies in breast cancer xenografts

Abstract Background. Breast carcinomas (BC) can have abnormal choline (Cho) metabolism. Earlier studies indicated that Cho uptake can differ between different subtypes of BC. The purpose of this study was to investigate uptake of 2-[18F]-fluoroethyl-choline ([18F]FECh) in three different patient-derived breast cancer xenografts (BCXs) using dynamic positron emission tomography (dPET). Material and methods. Nine athymic nude mice bearing bilateral MAS98.12 (basal-like), HBCx34 or MAS98.06 (both luminal B) BCXs were subjected to a 90-minute dPET scan following a bolus injection of 10 MBq of [18F]FECh. A Patlak Plot analysis and a well-established two-tissue compartment model were fitted to the uptake curves of the whole tumors, providing estimates of transfer rates between the vascular, non-metabolized and metabolized compartments. Patlak slope KP and intercept V, the rate constants k1, k2, k3, the intravascular fraction vb and MR[18F]FECh were estimated. Additionally, analyses of terminal blood samples and tumor cell suspension incubated with [18F]FECh were performed. Results. [18F]FECh uptake in all BCXs was similar to surrounding normal tissue, thus creating no image contrast. The average liver uptake was 10 times higher than the tumor uptake. The uptake in MAS98.12 was higher than in the other two BCXs during the whole course of the acquisition, and was significantly higher than in HBCx34 at 10–30 minutes after injection. No significant differences were found for k1, MR[18F]FECh and intravascular fraction vb. Patlak slope KP, k2 and k3 were significantly lower for the MAS98.12 xenograft, in line with in vitro results. KP was correlated with both MR[18F]FECh and k3. Conclusions. dPET demonstrated that different subtypes of breast cancer have different uptake of [18F]FECh. Differences in rate constants and KP were in line with in vitro uptake in cell suspensions and earlier spectroscopy and gene expression analysis.