PET Imaging of Somatostatin Receptors Using [⁶⁸GA]DOTA-d-Phe¹-Tyr³-Octreotide: First Results in Patients with Meningiomas

Materials and Methods

DOTA⁰-d-Phe¹-Tyr³-octreotide was synthesized as described in the literature (4). ⁶⁸Ga (half-life, 68.3 min; β⁺ 88%; Eβ⁺ maximum, 1,900 keV) was obtained in 0.5 mL 0.5N HCl from a ⁶⁸Ge/⁶⁸Ga radionuclide generator developed by our radiochemistry section. To this eluate 3 μL 1 mmol/L Ga³⁺ were added, followed by evaporation to dryness and redissolution in 200 μL 0.05 mol/L acetate buffer pH 4.8. [⁶⁸Ga]DOTATOC was prepared by adding 14 μL 1 mmol/L aqueous DOTATOC solution and heating the mixture for 15 min at 95°C. Subsequently, the pH was adjusted to 7.0 and uncomplexed ⁶⁸Ga was retained on a reversed phase cartridge (SepPAK; Waters Corp., Milford, MA), whereas [⁶⁸Ga]DOTATOC could be eluted with ethanol. After evaporation of the organic solvent, the compound was redissolved in 5.0 mL 0.01 mol/L phosphate-buffered saline pH 7.4. Specific activities obtained were 15–18 MBq ⁶⁸Ga/nmol of ligand. The preparations were checked by paper chromatography (Whatman No. 1 [Whatman, Maidstone, U.K.], methanol-to-water ratio, 55/45). Typically, >96% of the radioactivity migrated with an R_f ∼0.6 corresponding to [⁶⁸Ga]DOTATOC.

Before stereotactic radiotherapy, dynamic PET scans were acquired (ECAT EXACT HR⁺ [Siemens/CTI, Knoxville, TN]; 3D-Mode; 256 × 256 matrix; iterative ordered-subset expectation maximization reconstruction) over 120 min after intravenous bolus injection of 175 MBq [⁶⁸Ga]DOTATOC in 3 patients with 8 meningiomas (WHO I°; 7- to 25-mm diameters). After the nature of the procedure had been fully explained to them, written informed consent was obtained from all patients. The study was approved by the ethical committee of the University of Heidelberg (Heidelberg, Germany).

Venous blood samples were drawn at 5, 10, 30, 60, 90, and 120 min after injection for calculation of clearance data. Half-life α (0–10 min after injection) and half-life β (60–120 min after injection) of each patient were obtained from the time–activity curves by calculating least squares fits.

Stereotactic correlation allows a precise matching of CT, MRI, PET, and SPECT datasets even in the absence of anatomic structures, using an external reference system. The reference system must be compatible for all imaging modalities and positioning of the patient must be exactly reproducible. Each patient’s head was fixed in place using an individually shaped and tightly fitted fiber mask. For image fusion with the corresponding CT and MR images, we used an external acrylic localizer system consisting of 4 V-shaped tubes (0.8-mm inner diameter) filled with 30 MBq ¹⁴⁰Nd. ¹⁴⁰Nd decays with a half-life of 3.4 d to the positron emitter ¹⁴⁰Pr (half-life, 3.4 min).

Gadolinium-DTPA- (Magnevist, Schering AG, Berlin, Germany) enhanced MRI was performed on a 1.5-T whole-body MRI system (Magnetom SP; Siemens, Erlangen, Germany), acquiring T1- and T2-weighted spinecho sequences using the stereotactic localizer described previously in this article. Furthermore, CT scans were acquired before and after contrasting, with heads fixed in the localizer system. After fitting the external localizers, PET, CT, and MRI datasets were realigned. The tracer uptake was expressed as standardized uptake value:

Mean SUVs in regions of interest placed over meningiomas and pituitary glands (70% isocontour) as well as over both temporal lobes were calculated and corrected for partial volume effect.

Results

At 10 min after injection, about 80% of the [⁶⁸Ga]DOTATOC was rapidly cleared from blood because of extravasation with a half-life α of 3.5 min (renal clearance not included). Renal clearance of the compound showed a half-life β of 63 min.

The uptake in meningiomas as well as in pituitary glands increased rapidly after injection (Fig. 1A). At 20 min after injection the mean SUV reached 8.9 for meningiomas and 6.9 for pituitary glands. In meningiomas the SUVs reached a plateau between 60 and 120 min (range, 4.5–33.0; mean, 10.6 ± 9.6 [n = 8]). In contrast to this plateau, SUV of the pituitary glands further increased between 60 and 120 min after injection, from 9.1 to 11.4 (Fig. 1A).

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 1.

(A) Mean SUV for meningiomas, pituitary glands, and healthy brain tissue, 0–120 min after injection of 175 MBq [⁶⁸Ga]DOTATOC. (B) Contrast ratio of meningiomas to healthy brain tissue, 0–120 min after injection. (C) Coronal, transaxial, and sagittal PET scans of two intraventricular (arrowheads) and one parietal meningioma (arrow). Stereotactic localizer system surrounding skull. (D) Physiologic SSTR expression of pituitary gland (arrowheads) and meninges (arrows). Stereotactic localizer-system surrounding skull.

Because of the intact blood–brain barrier, we found no accumulation of [⁶⁸Ga]DOTATOC in the surrounding brain tissue (mean SUV, 0.05 ± 0.04) later than 10 min after injection. The ratio of uptake in the meningiomas to uptake in the brain tissue showed an exponential rise to a maximum of 730 at 120 min after injection (Fig. 1B).

All meningiomas, including small lesions (3 meningiomas; diameter range, 7–8 mm) showed high tracer uptake and could clearly be separated from surrounding brain and bone tissues (Fig. 2). Tracer boundaries showed a good correspondence with the matched CT and MR images. Meningiomas may pose serious problems because of local osseous invasiveness. Compared with the morphological techniques, PET provides valuable additional information regarding the extent of meningiomas located beneath osseous structures, especially at the skull base (Fig. 2).

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 2.

(A) Realigned CT, PET, and MRI scans of medial temporal/sphenoidal meningioma (arrow) beneath pituitary gland (arrowhead). (B) Image fusion of same patient (color coded, PET; black and white, MRI).

Discussion

Using [⁶⁸Ga]DOTATOC PET, all meningiomas could be identified as lesions with very high tumor-to-background ratios. Even small meningiomas (7-mm diameter) showed high tracer uptake and could clearly be delineated from bone, healthy brain, and soft tissues. Therefore, [⁶⁸Ga]DOTATOC PET seems to be a promising method to overcome the previously reported (3) difficulties of [¹¹¹In]DTPAOC SPECT in detecting meningiomas with diameters < 2.7 cm. Besides the higher resolution of the PET method compared with SPECT, a further improvement is caused by the receptor binding characteristics of the DOTATOC compounds, as was recently shown in vitro (5). A marked increase of SSTR₂ affinity was found for [Ga]DOTATOC (IC₅₀ 2.5 nmol/L) compared with the Y-labeled compound (IC₅₀ 11 nmol/L) as well as with [In]DTPAOC (IC₅₀ 22 nmol/L).

Using PET, the possibility of calculating absolute as well as relative quantitative parameters might facilitate the differentiation between meningiomas and pituitary adenomas as suggested for [¹¹¹In]DTPAOC SPECT (2). Clinical applications of this SSTR-imaging technique may lead to improved characterization of tumors near the base of the skull in cases of unclear MRI findings in tumors to be treated by radiosurgery alone or in patients at high risk for stereotactic biopsy. In this setting, a differentiation between meningiomas and neurinomas or optic nerve gliomas, as well as a differentiation between multifocal diseases (cerebral metastases, neurofibromatosis type II) would be desirable (2). Furthermore, the assessment of SSTR density may be used for a noninvasive grading of meningiomas and for the planning of surgery or stereotactic radiotherapy to delineate the extent of meningiomatous manifestation and to differentiate meningeal infiltration from meningeal reaction. In the follow-up of patients after surgery or stereotactic radiotherapy, distinguishing scar tissue from necrosis and meningioma recurrence could have a significant impact on determining treatment for patients (2). All those applications for [¹¹¹In]DTPAOC SPECT could benefit from the better spatial resolution, the higher sensitivity, and the possibility of quantification provided by [⁶⁸Ga]DOTATOC PET. Diagnosis of neuroendocrine tumors, including search for primaries and metastases as well as the dosimetry performed before [⁹⁰Y]DOTATOC radionuclide therapy might be a further important application of [⁶⁸Ga]DOTATOC PET. The clinical impact of this new PET tracer compared with [¹¹¹In]DTPAOC has to be evaluated in further studies.

Conclusion

According to our initial experiences in a limited number of patients, [⁶⁸Ga]DOTATOC seems to be a very promising new PET tracer for imaging SSTRs even in small meningiomas. It offers excellent imaging properties and very high tumor-to-background ratios. Additionally, labeling of the ligand with ⁶⁸Ga is easy to perform and generator production of the tracer may ensure its continuous availability. Further evaluation of [⁶⁸Ga]DOTATOC in a larger number of patients seems to be justified.