Advantages and Limits of Targeted Radionuclide Therapy with Somatostatin Antagonists
| Autor: | Magalie Haissaguerre, Clément Morgat, Elif Hindié, Paolo Zanotti-Fregonara, Antoine Tabarin, Laurence Bordenave |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Agonist
medicine.drug_class Adenosinergic Pharmacology Adenosine 030218 nuclear medicine & medical imaging 03 medical and health sciences Adenosine A1 receptor chemistry.chemical_compound 0302 clinical medicine Preladenant chemistry In vivo 030220 oncology & carcinogenesis Radioligand medicine Radiology Nuclear Medicine and imaging Endogenous agonist medicine.drug |
| Zdroj: | Journal of Nuclear Medicine. 59:546-547 |
| ISSN: | 2159-662X 0161-5505 |
| Popis: | 546 Objectives: The adenosine A1 receptor (A1R) is implicated in sleep modulation and highly expressed in the brain. When activated by its endogenous agonist, adenosine, A1R blocks neurotransmitter release, reduces neuron firing rate, and has a negative chronotropic effect in the heart. Further examination of the role of the A1R in the sleep-wake cycle would require a PET radiotracer capable of indicating subtle changes in the levels of endogenous adenosine. Although A1R PET radioligands have been heavily studied, the current well-established ones are all A1R antagonists based on a xanthine core structure. These antagonists, however, fail to compete with adenosine, most likely due to having different binding sites. Meanwhile, no successful A1R agonist tracer has been developed. Since most agonists are derived from a purine nucleoside, the hydrophilic ribose makes these compounds difficult to cross the blood-brain barrier (BBB) at low concentrations. Here we report the synthesis of the first non-xanthine, non-nucleoside A1R agonist radiotracer, as well as its use in preclinical PET studies. Methods: 4-Phenylpyridine and 4-phenlypyrimidine were chosen as templates and sixteen compounds were generated through parallel synthesis. In vitro structure-activity relationship (SAR) studies were performed to screen their A1R/A2AR binding and functional activities. Preliminarily, four selected compounds were radiolabeled to test their BBB permeability and biodistribution in the rat brain (Wistar), followed by PET scans conducted on a Focus-220 scanner to assess their pharmacokinetics, in vivo binding affinities, specificity (self-blocking study), and selectivity over A2AR (blocking study with Preladenant, a selective A2AR antagonist). Results: Compound 8 appears to be a potent and selective partial A1R agonist based on in vitro data (hA1R Ki=0.8 nM, hA1R % activation at 10 μM=11.8 %, hA2AR % replacement at 10 μM= 74.5%). [11C]8 was synthesized with its desmethyl precursor and [11C]CH3I in moderate radiochemical yield (RCY=18±4%, n=6), high radiochemical purity (>99%) and superior specific activity (18.5±7.0 Ci/µmol @EOB, n=25). [11C]8 showed great BBB permeability (SUV, ~1 g/mL at 10 min after iv administration, logD7.4=3.26) and test-retest reproducibility in the rat brain (n=3). Brain uptake of [11C]8 was blocked significantly by non-radioactive compound 8 pretreatment (iv, 1 mg/kg, n=3), but not Preladenant (selective A2AR antagonist) pretreatment, which reflects high A1R selectivity (Figure 1). Conclusion: We developed the first adenosine A1R agonist radioligand, [11C]8, for CNS applications. Rodent PET studies demonstrated that [11C]8 has excellent in vivo properties and further brain studies on competitive inhibition by endogenous adenosine are under way. This radiotracer might not only be a useful tool to investigate the roles of A1R and endogenous adenosine in sleep mechanisms, but may also be a good drug template for adenosinergic abnormalities. Figure 1. Structure of [11C]8 and representative rat brain PET scan |
| Databáze: | OpenAIRE |
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