99m Tc-CXCR4-L for Imaging of the Chemokine-4 Receptor Associated with Brain Tumor Invasiveness: Biokinetics, Radiation Dosimetry, and Proof of Concept in Humans

• Published in: Contrast media and molecular imaging Vol. 2020; pp. 1 - 10
• Main Authors: Vallejo-Armenta, Paola, Santos-Cuevas, Clara, Soto-Andonaegui, Juan, Villanueva-Pérez, Rosa M., González-Díaz, Jorge I., García-Pérez, Francisco O., Arrellano-Zarate, Angélica, Luna-Gutiérrez, Myrna, Azorín-Vega, Erika, Ocampo-García, Blanca, Ferro-Flores, Guillermina
• Format: Journal Article
• Language: English
• Published: 27.04.2020
• ISSN: 1555-4309; 1555-4317
• DOI: 10.1155/2020/2525037

Overexpression of the chemokine-4 receptor (CXCR4) in brain tumors is associated with high cancer cell invasiveness. Recently, we reported the preclinical evaluation of 99m Tc-CXCR4-L (cyclo-D-Tyr-D-[NMe]Orn[EDDA- 99m Tc-6-hydrazinylnicotinyl]-Arg-NaI-Gly) as a SPECT radioligand capable of specifically detecting the CXCR4 protein. This research aimed to estimate the biokinetic behavior and radiation dosimetry of 99m Tc-CXCR4-L in healthy subjects, as well as to correlate the radiotracer uptake by brain tumors in patients, with the histological grade of differentiation and CXCR4 expression evaluated by immunohistochemistry. 99m Tc-CXCR4-L was obtained from freeze-dried kits prepared under GMP conditions (radiochemical purities >97%). Whole-body scans from six healthy volunteers were acquired at 0.3, 1, 2, 4, 6, and 24 h after 99m Tc-CXCR4-L administration (0.37 GBq). Time-activity curves of different source organs were obtained from the image sequence to adjust the biokinetic models. The OLINDA/EXM code was employed to calculate the equivalent and effective radiation doses. Nine patients with evidence of brain tumor injury (6 primaries and 3 recurrent), determined by MRI, underwent cerebral SPECT at 3 h after administration of 99m Tc-CXCR4-L (0.74 GBq). Data were expressed as a T / B (tumor uptake/background) ratio. Biopsy examinations included histological grading and anti-CXCR4 immunohistochemistry. Results showed a fast blood activity clearance ( T 1/2 α  = 0.81 min and T 1/2 β  = 12.19 min) with renal and hepatobiliary elimination. The average equivalent doses were 6.10 E  − 04, 1.41 E  − 04, and 3.13 E  − 05 mSv/MBq for the intestine, liver, and kidney, respectively. The effective dose was 3.92 E  − 03 mSv/MBq. SPECT was positive in 7/9 patients diagnosed as grade II oligodendroglioma (two patients), grade IV glioblastoma (two patients), grade IV gliosarcoma (one patient), metastasis, and diffuse astrocytoma with T / B ratios of 1.3, 2.3, 13, 7, 19, 5.5, and 3.9, respectively, all of them with positive immunohistochemistry. A direct relationship between the grade of differentiation and the expression of CXCR4 was found. The two negative SPECT studies showed negative immunohistochemistry with a diagnosis of reactive gliosis. This “proof-of-concept” research warrants further clinical studies to establish the usefulness of 99m Tc-CXCR4-L in the diagnosis and prognosis of brain tumors.