Radiolabeling and Preliminary In Vivo Evaluation of the Candidate CCR2 Targeting PET Radioligand [<sup>11</sup>C]AZD2423
Background: AZD2423 is a high-affinity and selective negative allosteric modulator of the chemokine receptor type 2 (CCR2). This receptor plays important roles in the extravasation and transmigration of monocytes under inflammatory conditions. The aims of the current positron emission tomography (PE...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/2/135 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Background: AZD2423 is a high-affinity and selective negative allosteric modulator of the chemokine receptor type 2 (CCR2). This receptor plays important roles in the extravasation and transmigration of monocytes under inflammatory conditions. The aims of the current positron emission tomography (PET) study were as follows: (i) to develop an efficient synthetic method for labeling AZD2423 with carbon-11 (<sup>11</sup>C, t<sub>1/2</sub> = 20.4 min) and (ii) to evaluate its potential to visualize CCR2 binding in the non-human primate (NHP) brain. Methods: [<sup>11</sup>C]AZD2423 was synthesized using a novel two-step, two-pot [<sup>11</sup>C]carbon monoxide carbonylation procedure. PET imaging studies in NHPs (n = 2) were conducted to assess its brain penetration and in vivo distribution. Results: Radiolabeling of [<sup>11</sup>C]AZD2423 was accomplished with good yield (7.4 ± 0.6%, n = 4) and high radiochemical purity (>99%) using [<sup>11</sup>C]carbon monoxide. Preliminary PET imaging in NHPs revealed low [<sup>11</sup>C]AZD2423 brain exposure under both baseline and pretreatment conditions (SUV<sub>peak</sub> = 0.4, n = 2). However, high concentrations of radioactivity were observed in organs outside the brain at baseline, e.g., the thyroid gland (SUV<sub>peak</sub> = 3.3, n = 2), parotid gland (SUV<sub>peak</sub> = 3.4, n = 2), and submandibular gland (SUV<sub>peak</sub> = 4.4, n = 2). This radioactivity was markedly reduced following pretreatment with AZD2423 (3.0 mg/kg), indicating specific binding of [<sup>11</sup>C]AZD2423 to CCR2 in vivo. The presence of specific CCR2 binding was further validated using two-tissue compartment modeling, which demonstrated a 59–63% reduction in the total volume of distribution values in the analyzed peripheral tissues. Conclusions: Altogether, [<sup>11</sup>C]AZD2423 shows potential as a PET radioligand for the in vivo visualization of CCR2 expression in tissues outside the brain and may also serve as a lead compound for the further development of a CCR2 PET radioligand suitable for brain imaging. |
|---|---|
| ISSN: | 1424-8247 |