^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

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.

Current State of Targeted Radiometal-Based Constructs for the Detection and Treatment of Disease in the Brain

“…22 This finding is interesting, as CXCR2 may also prove to be a novel target for the disease. 23,24 In addition to taking advantage of disease systems disrupting the BBB themselves, another alternative method to target brain disease is to investigate auxiliary delivery routes. Currently, the main route of delivery tends to be through intravenous injection.…”

“…For example, in multiple sclerosis, during inflammation it is possible that brain endothelial CXCR2 contributes to BBB disturbance . This finding is interesting, as CXCR2 may also prove to be a novel target for the disease. , …”

“…The immunohistochemistry of the expression of CXCR4 in the patients' lesions corroborated the proportional relationship between CXCR4 expression and CXCR4-L uptake. 24 Somatostatin analogues have been investigated as potential vectors for the SR-2 receptor that has demonstrated expression on human gliomas. 59 DOTATOC is a somatostatin analogue with a DOTA moiety.…”

“…99m Tc-CXCR4-L (Figure ) showed targeted uptake and allowed for discrimination between tumor and gliosis. The immunohistochemistry of the expression of CXCR4 in the patients’ lesions corroborated the proportional relationship between CXCR4 expression and CXCR4-L uptake …”

Der Chemokinrezeptor CXCR4 – seine Entwicklung und Bedeutung in der nuklearmedizinischen Theranostik

“…Ebenso die BHS-Passage adressierend wurde im Jahr 2020 das sich auf einer 6-Hydrazinylnicotinamid-Einheit (HYNIC) gründende theranostische Duo [99 m Tc] Tc-/[ 177 Lu]Lu-CXCR4-L[47], dessen Strukturgerüst abseits des Chelators jenem des Pentixafors mit Ausnahme eines Stereozentrums gleicht, untersucht. 7 /9 Patienten einer Kohorte mit Glioblastomen und Astrozytomen unterschiedlichen klinischen Grades wurden basierend auf der Auswertung ihrer SPECT-Aufnahmen in Übereinstimmung mit ihren immunhistochemischen Befunden als CXCR4-postiv bewertet[101]. Ein weiteres theranostisches Duo, welches in präklinischen Untersuchungen mit nanomolaren CXCR4-Affinitäten, einer guten in vivo-Stabilität und einem guten Tumor/Untergrundverhältnis vielverspre-…”