[99mTc]Tc-iPSMA SPECT brain imaging as a potential specific diagnosis of metastatic brain tumors and high-grade gliomas.

BACKGROUND: PSMA (prostate-specific membrane antigen) protein is heavily expressed in the proliferating microvasculature of high-grade gliomas (HGG) and brain metastases (BM). This research aimed to assess [99mTc]Tc-iPSMA SPECT brain imaging as a potential specific diagnosis of HGG and BM by PSMA-targeting in their proliferating vasculature. METHODS: Forty-one patients, with suspected brain tumors, as detected by enhanced MRI scanning, were enrolled to undergo preoperative [99mTc]Tc-iPSMA SPECT brain imaging. Semiquantitative image analyses, to evaluate the maximum target-to-background ratio (TBRmax), were performed. All diagnoses were histopathologically confirmed. PSMA expression was evaluated by immunohistochemistry (IHC) in 11 brain tumor tissues. TBRmax values were correlated with IHC results and tumor WHO grade (HGG vs LGG). RESULTS: [99mTc]Tc-iPSMA images showed increased uptake in BM, HGG, and recurrent gliomas (TBRmax of 25.1 ± 7.1, 18.5 ± 9.0, 15.0 ± 9.9, respectively), and was negative in treatment-naive patients with LGG and reactive gliosis. PSMA was highly expressed in the vascular endothelium of grade IV gliomas and BM, while its expression was extremely low in LGG and completely absent in gliosis. By using 2.8 as a threshold value for TBRmax, the specificity, sensitivity, PPV, NPV and accuracy were 100%, 94%, 100%, 77% and 95%, respectively. CONCLUSIONS: The results of this pilot study show that [99mTc]Tc-iPSMA SPECT brain imaging is a specific and potentially useful neuroimaging tool for assessing tumoral neovasculature formation in gliomas and brain metastases.

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

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 (T 1/2 α = 0.81 min and T 1/2 ß = 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.