Synthesis, Radiolabeling, and Biological Evaluation of 5‑Hydroxy-2‑[¹⁸F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

Aiming at developing mechanism-based amino acid ¹⁸F-PET tracers for tumor imaging, we synthesized two ¹⁸F-labeled analogues of 5-hydroxy-l-[β-¹¹C]­tryptophan ([¹¹C]­5HTP) whose excellent in vivo performance in neuroendocrine tumors is mainly attributed to its decarboxylation by aromatic amino acid decarboxylase (AADC), an enzyme overexpressed in these malignancies. Reference compounds and precursors were synthesized following multistep synthetic approaches. Radiosynthesis of tracers was accomplished in good radiochemical yields (15–39%), high specific activities (45–95 GBq/μmol), and excellent radiochemical purities. In vitro cell uptake was sodium-independent and was inhibited ≥95% by 2-amino-2-norbornanecarboxylic acid (BCH) and ∼30% by arginine. PET imaging in mice revealed distinctly high tumor/background ratios for both tracers, outperforming the well-established <i>O</i>-(2-[¹⁸F]­fluoroethyl)­tyrosine ([¹⁸F]­FET) tracer in a head-to-head comparison. Biological evaluation revealed that the in vivo performance is most probably independent of any interaction with AADC. Nevertheless, the excellent tumor visualization qualifies the new tracers as interesting probes for tumor imaging worthy for further investigation

Synthesis and Pharmacological Evaluation of [¹¹C]Granisetron and [¹⁸F]Fluoropalonosetron as PET Probes for 5‑HT₃ Receptor Imaging

Serotonin-gated ionotropic 5-HT₃ receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT₃ receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the “setrons”) that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (<b>15</b>) that has a binding affinity (<i>K</i>_i = 0.26 ± 0.05 nM) similar to the parent drug (<i>K</i>_i = 0.21 ± 0.03 nM). We radiolabeled <b>15</b> by nucleophilic ¹⁸F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-¹¹<i>C</i>)-<i>N</i>-granisetron ([¹¹C]<b>2</b>) through <i>N</i>-alkylation with [¹¹C]­CH₃I, respectively. Both compounds [¹⁸F]<b>15</b> (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [¹¹C]<b>2</b> (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [¹⁸F]<b>15</b> and [¹¹C]<b>2</b> revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT₃ receptors at significant levels. Subsequent PET experiments suggested that [¹⁸F]<b>15</b> and [¹¹C]<b>2</b> are of limited utility for the PET imaging of brain 5-HT₃ receptors in vivo