János Marton

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.

Synthesis and Evaluation of 18F-FE-PEO in Rodents: An 18F-Labeled Full Agonist for Opioid Receptor Imaging

We have investigated the opioid receptor (OR) agonist (20R)-4,5-α-epoxy-6-(2-18F-fluoroethoxy)-3-hydroxy-α,17-dimethyl-α-(2-phenyleth-1-yl)-6,14-ethenomorphinan-7-methanol (18F-FE-PEO) as a candidate OR PET ligand. This tracer is attractive because it combines 18F labeling, is suited to the slow kinetics of high-affinity ligands, and has agonist binding, which has been shown to be more sensitive to changes in OR occupation than is antagonist binding. Methods: Agonist potency and off-target binding were investigated in vitro, and autoradiographic studies on rat brain sections were used to assess binding patterns. Quantification of the tracer in vivo was investigated using small-animal PET in rats with blood sampling. Results: 18F-FE-PEO was obtained by direct nucleophilic radiofluorination and subsequent deprotection with a yield of 28% ± 15%, a specific activity of 52–224 MBq/nmol, and a radiochemical purity of more than 97% (90 min from end of bombardment). In vitro studies showed it to be a full agonist ligand, which selectively binds to OR with high affinity, although it is not selective to a single OR subtype (inhibition constant, 0.4–1.6 nM across OR subtypes). Autoradiography binding patterns were consistent with the known distribution of OR, although nondisplaceable signal typically constituted one third of the signal in OR-dense regions. Although metabolites were present in blood (∼40% of plasma radioactivity was nonparent 3 h after injection), no significant metabolite fraction was found in brain tissue, aiding PET quantification. A plasma input 2-tissue-compartment model provided good fits to the PET data, and regional distribution volumes from the latter correlated well with those from Logan plot analysis (r2 = 0.98). The cerebellum had the lowest distribution volume, but the time–activity curve data could not be adequately fitted with a 1-tissue-compartment model. Reference tissue models using the cerebellum as the reference region did not provide good fits to the data, so blood-based kinetic analysis is recommended. Conclusion: As the first 18F-labeled OR agonist ligand, 18F-FE-PEO is a useful addition to the existing OR ligand portfolio.

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.

A Convenient Route to 4-Carboxy-4-Anilidopiperidine Esters and Acids

The route selection and development of a convenient synthesis of 4-carboxy-4-anilidopiperidines is described. Previous routes were hampered by the low yield of the target esters as well as the inability to convert the esters to the required free acids. Considerations for large-scale production led to a modified synthesis that utilised a tert-butyl ester of 4-carboxy-4-anilidopiperidines which resulted in a dramatic increase in the overall yield of the target N-propionylated- 4-anilidopiperidine-4-carboxylic acids and their corresponding methyl esters. These compounds are now available for use as precursors and reference standards, of particular value for the production of 11C and 18F-labelled 4-carboxy-4-anilidopiperidine radiotracers.