18F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT1A receptor agonist for PET neuroimaging

Brain Struct Funct. 2018 Jul;223(6):2973-2988. doi: 10.1007/s00429-018-1672-7. Epub 2018 May 5.

Abstract

Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerative disorders. Currently, all available 5-HT1A receptor PET radiopharmaceuticals that are radiolabeled with fluorine-18 are antagonists. As agonists bind preferentially to the high-affinity state of receptors, it would be of great interest to develop agonist radioligands which could provide a measure of the functional 5-HT1A receptors in pathophysiological processes. The 5-HT1A receptor agonist candidates we recently proposed had promising in vitro properties but were not optimal in terms of PET imaging. F13640, a.k.a befiradol or NLX-112, is a 5-HT1A receptor agonist with a high affinity (Ki = 1 nM) and a high selectivity that would be suitable for a potential PET radiopharmaceutical. With propose here the first preclinical evaluation of 18F-F13640. 18F-F13640's nitro-precursor was synthesized and radiolabeled via a fluoro-nucleophilic substitution. Its radiopharmacological characterization included autoradiographic studies, metabolic studies, and in vivo PET scans in rat, cat and non-human primate. Some of the results were compared with the radiotracer 18F-MPPF, a 5-HT1A receptor antagonist. The radiochemical purity of 18F-F13640 was > 98%. In vitro binding pattern was consistent with the 5-HT1A receptor distribution. Metabolic studies revealed that the radiotracer rapidly entered the brain and led to few brain radiometabolites. Although 18F-F13640 in vivo binding was blocked by the 5-HT1A antagonist WAY-100635 and the 5-HT1A agonist 8-OH-DPAT, the distribution pattern was markedly different from antagonist radiotracers in the three species, suggesting it provides novel information on 5-HT1A receptors. Preliminary studies also suggest a high sensitivity of 18F-F13640 to endogenous serotonin release. 18F-F13640 has suitable characteristics for probing in vitro and in vivo the 5-HT1A receptors in high-affinity state. Quantification analyses with kinetic modeling are in progress to prepare the first-in-man study of 18F-F13640.

Keywords: Agonist; Cat; PET tracer; Primate; Rat; Serotonin 1A receptor.

MeSH terms

  • Animals
  • Autoradiography
  • Binding, Competitive / drug effects
  • Brain / diagnostic imaging*
  • Brain / drug effects
  • Brain / metabolism
  • Brain Mapping*
  • Cats
  • Female
  • In Vitro Techniques
  • Macaca mulatta
  • Male
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics*
  • Positron-Emission Tomography / methods*
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / pharmacokinetics*
  • Species Specificity
  • Time Factors
  • Tissue Distribution / drug effects

Substances

  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • 4-(2'-methoxyphenyl)-1-(2'-(N-2'-pyridinyl)-p-(18F)fluorobenzamido )ethylpiperazine