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

Abstract EN

Overexpression of the chemokine-4 receptor (CXCR4) in brain tumors is associated with high cancer cell invasiveness.

Recently, we reported the preclinical evaluation of 99mTc-CXCR4-L (cyclo-D-Tyr-D-[NMe]Orn[EDDA-99mTc-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 99mTc-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.

99mTc-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 99mTc-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 99mTc-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 (T1/2α = 0.81 min and T1/2β = 12.19 min) with renal and hepatobiliary elimination.

The average equivalent doses were 6.10E − 04, 1.41E − 04, and 3.13E − 05 mSv/MBq for the intestine, liver, and kidney, respectively.

The effective dose was 3.92E − 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 99mTc-CXCR4-L in the diagnosis and prognosis of brain tumors.