Wolfgang Brandau

68Ga-DOTATOC Versus 68Ga-DOTATATE PET/CT in Functional Imaging of Neuroendocrine Tumors

Radiolabeled somatostatin analogs represent valuable tools for both in vivo diagnosis and therapy of neuroendocrine tumors (NETs) because of the frequent tumoral overexpression of somatostatin receptors (sst). The 2 compounds most often used in functional imaging with PET are 68Ga-DOTATATE and 68Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in vitro affinity of 68Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately 10-fold higher than that of 68Ga-DOTATOC. This difference may affect their efficiency in the detection of NET lesions because it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs (68Ga-DOTATATE and 68Ga-DOTATOC) in the same NET patients. Methods: Forty patients with metastatic NETs underwent 68Ga-DOTATOC and 68Ga-DOTATATE PET/CT as part of the work-up before prospective peptide receptor radionuclide therapy. The performance of both imaging methods was analyzed and compared for the detection of individual lesions per patient and for 8 defined body regions. A region was regarded positive if at least 1 lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUVmax) was compared for concordant lesions and renal parenchyma. Results: Seventy-eight regions were found positive with 68Ga-DOTATATE versus 79 regions with 68Ga-DOTATOC (not significant). Overall, however, significantly fewer lesions were detected with 68Ga-DOTATATE than with 68Ga-DOTATOC (254 vs. 262, P < 0.05). Mean 68Ga-DOTATATE SUVmax across all lesions was significantly lower than 68Ga-DOTATOC (16.0 ± 10.8 vs. 20.4 ± 14.7, P < 0.01). Mean SUVmax for renal parenchyma was not significantly different between 68Ga-DOTATATE and 68Ga-DOTATOC (12.7 ± 3.0 vs. 13.2 ± 3.3). Conclusion: 68Ga-DOTATOC and 68Ga-DOTATATE possess a comparable diagnostic accuracy for the detection of NET lesions, with 68Ga-DOTATOC having a potential advantage. The approximately 10-fold higher affinity for the sst2 of 68Ga-DOTATATE does not prove to be clinically relevant. Quite unexpectedly, SUVmax of 68Ga-DOTATOC scans tended to be higher than their 68Ga-DOTATATE counterparts.

Comparison of technetium 99m polyclonal human immunoglobulin and technetium 99m monoclonal antibodies for imaging chronic osteomyelitis. First clinical results.

The accuracy of technetium-99m human immunoglobulin (HIG) for the detection of chronic osteomyelitis (OM) was compared with white blood cell scintigraphy using99mTc-labelled monoclonal mouse antibodies (MAB). Seventeen patients suspected of having OM in 20 lesions went through three-phase skeletal scintigraphy, HIG scintigraphy and MAB scintigraphy. The final diagnosis was established by open surgery, histology and bacteriology. Chronic OM was proved in 14/20 lesions. Six of these 14 infections were located in peripheral areas without active bone marrow and 8/14 in central areas with active bone marrow. In peripheral OM, 5/6 with HIG and 6/6 with MAB were true positives. In the central skeleton all 8/8 infections appeared as cold lesions in the MAB study, which were defined as being false negative due to their non-specificity. Using HIG, 5/8 central infections were determined to be truly positive by showing photon-rich lesions. These 5 lesions were located in the hip region and in the pelvis, whereas 3 lesions of the spine were missed. There were no false-positive results in either studies. In conclusion, MAB was superior to HIG in peripheral OM concerning sensitivity, anatomical landmarks and differentiation of soft tissue versus bone infection. In central OM MAB detected all lesions accurately, but no differential diagnosis was possible due to the non-specificity of photon-low areas. In this respect HIG seems to be more specific due to the increased accumulation even in central infection sites.

Non-invasive grading of primary brain tumours: Results of a comparative study between SPET with123I-α-methyl tyrosine and PET with18F-deoxyglucose

Use of iodine-123-α-methyl tyrosine (123I-IMT) allows investigation of the amino acid transport rate in gliomas. It was the aim of this study to compare the value of measurement of glucose metabolism with that of measurement of123I-IMT uptake for the non-invasive grading of brain tumours. The study population comprised 23 patients with histopathologically proven primary brain tumours; 14 had high-grade gliomas, and nine low-grade brain neoplasms. Glucose metabolism was studied using an ECAT EXACT 47 positron emission tomography (PET) camera and fluorine-18 fluorodeoxyglucose (18F-FDG);123I-IMT uptake was measured with the triple-headed single-photon emission tomography (SPET) camera, MULTISPECT 3.18F-FDG and123I-IMT uptake was quantified as ratios between the uptake by the tumour and contralateral regions of reference. Glucose metabolism and amino acid uptake of the brain tumours correlated significantly (r=0.71,P <0.001). Assuming discrimination thresholds between high-grade and low-grade tumours of 0.8 for18F-FDG uptake and 1.8 for123I-IMT uptake, the accuracy values of18F-FDG PET and123I-IMT SPET for differentiating between high-grade and low-grade tumours were 21/23 (91%) and 19/23 (83%), respectively. The difference in diagnostic performance was not significant on receiver operating characteristic analysis (P >0.4). It is concluded that there is no major difference between the PET investigation of glucose metabolism and the less expensive SPET measurement of amino acid uptake in terms of their accuracy in evaluating the malignancy grade of primary brain tumours. This encourages the performance of further studies to analyse the potential impact of123I-IMT SPET on the therapeutic management of patients with brain tumours.

Assessment of Lesion Response in the Initial Radioiodine Treatment of Differentiated Thyroid Cancer Using 124I PET Imaging

124I PET/CT images from differentiated thyroid cancer patients were retrospectively analyzed to assess the relationship between absorbed radiation dose (AD) to lesions and their response after radioiodine therapy. Methods: Patients received serial 124I PET/CT scans before and after their first radioiodine treatment. The pretherapy PET data were used to segment the lesion volumes and to predict the therapy-delivered ADs after administration of the therapeutic 131I activity. The segmentation method’s lower volume limit of determinability was a sphere of 0.80 mL, which classified the lesions into a known-volume group (>0.80 mL) or a small-volume group (≤0.80 mL) with their respective average and minimum ADs. The posttherapy PET data were used to assess the lesion-based therapy success. In the known-volume group, the response rate was calculated on the basis of lesions that received average ADs above the generally accepted threshold of 85 Gy for metastases and 300 Gy for thyroid remnants (TRs) and was expressed as the percentage of completely responding lesions. In the small-volume group, the metastasis and TR responses were evaluated for 3 minimum-AD groups: 5 to 10 Gy (TR, 5 to 30 Gy), >10 to 85 Gy (TR, >30 to 300 Gy), and >85 Gy (TR, >300 Gy). Their response rates were calculated in terms of the percentage of completely responding lesions in each minimum-AD group. Results: In total, 59 lesions in 17 patients were amenable to reliable volume estimation. The response rates were 63%, 88%, and 90% for lymph node metastases (LMs), pulmonary metastases, and TRs, respectively. The response rates of 168 small lesions in 34 patients were more than 82% for LMs and more than 91% for TRs in each of the 3 minimum-AD groups; all small pulmonary metastases responded completely. Conclusion: In the known-volume group, the response rate for TRs matched well with historical data derived using 131I scintigraphy imaging, whereas the response rate for LMs was not as high as expected, which may be explained by too short a follow-up time for a few LMs and a higher sensitivity of PET imaging. Small lesions were treated effectively, suggesting that they are considerably smaller than 0.80 mL.

In vitro studies on the cellular uptake of melanoma imaging aminoalkyl-iodobenzamide derivatives (ABA)

The cellular uptake of 11 radioiodinated aminoalkyl-iodobenzamides (ABA) was studied using cultivated murine melanoma cells (B16/C3). All derivatives showed a high uptake (up to about 80%) of radioactivity in melanotic melanoma cells; hence, accumulation of all compounds radioiodinated in the ortho position was reduced by approximately 30%. Using the compound para-[131I]iododiethyl-aminoethylbenzamide (p-131I-ABA-2-2) a close correlation of the cellular melanin content with the tracer uptake (R2 = 0.95) was verified. The presence of extracellular melanin, however, had no effect on the cellular tracer uptake. Because the accumulation was independent of the specific activity of p-131I-ABA-2-2, a significant contribution to the uptake process by binding to receptor sites could be excluded.

Malignant Pheochromocytoma Imaging with [124I]mIBG PET/MR

Pheochromocytoma localized in the adrenal medulla (in 85%) or in the thoracic/abdominal sympathetic trunk (paraganglioma) has malignant potential in about 10% of cases. Metaiodobenzylguanidine (mIBG) can be labeled with 123-iodine (for scintigraphy), 131-iodine (basically for therapy), or 124-iodine [excellent positron emission tomography (PET) imaging and tumor dosimetry based on high spatial resolution] and has high sensitivity for the diagnosis of primary/metastatic pheochromocytoma (1–3). Thiscasereportsontheworldwidefirst [I]-mIBG-PET/ magnetic resonance imaging (MRI) performed with an integrated PET/MR (Biograph mMR; Siemens Healthcare, Erlangen, Germany) in a malignant pheochromocytoma. The addition of MRI to mIBG-PET is promising as it improves tumor delineation because of the high soft tissue contrast in MRI that is especially relevant in pretherapeutic dosimetry. Compared with conventional [I]mIBG scintigraphy, [I]mIBG-PET provides high-resolution images. A 24-yr-old woman suffering from progressive malignant pheochromocytoma (primary right adrenal) underwent dosimetry with [I]mIBG PET/computed tomography (CT) (50 MBq) for treatment planning before therapy with [I]mIBG. An additional whole-body PET/ MRI (48 h after [I]mIBG administration) was performed with the following examination parameters (entire acquisition time, 40 min): four bed positions (head to upper thigh); PET, 8-min list mode per bed position; MRI, DIXON (T1-weighted sequences in-/opposed phases) for acquiring the -map for attenuation correction, simultaneous with PET non-contrast-enhanced coronal T1, transversal fat-saturated T2, and diffusionweighted imaging non-simultaneous followed by coronal and axial fat-saturated T1 after administration of gadolinium-based contrast agent. The PET/MRI (Fig. 1A, PET maximum intensity projection (MIP); B, fused PET/MRI coronal T1; C, fused PET/CT coronal) revealed local tumor recurrence (right adrenal bed) and multiple metastases (liver, lymph nodes, abdominal muscles, peritoneal) with intense tracer uptake, hyperintense signal on T2, hypointense on nonen-

Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors.

PURPOSE Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET. PATIENTS AND METHODS Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma. RESULTS Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 ± 6.8 versus 22.1 ± 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 ± 2.6 versus 12.6 ± 2.7). CONCLUSIONS (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors.

N-(2-diethylaminoethyl)-4-[123I]iodobenzamide as a tracer for the detection of malignant melanoma: simple synthesis, improved labelling technique and first clinical results.

In order to evaluate the behaviour of N-(2-diethylaminoethyl)-4-[123I]iodobenzamide in malignant melanotic disease, we synthesized the bromo compound in a simple one-step reaction. Labelling was performed by non-isotopic bromine-iodine-123 exchange in radiochemical yields up to 60%. By means of isocratic high-performance liquid chromatography, the iodinated product could be isolated with high apparent specific activity. First clinical studies in patients with malignant melanoma using N-(2-diethylaminoethyl)-4[123I]iodobenzamide showed moderate uptake of the tracer in the tumour and the suspected metastases in all patients. Most of the lesions were detectable with technetium-99m-diethylene triamine penta-acetic acid (DTPA) scintigraphy too, but we were able to detect additional, previously unidentified metastases with benzamide scintigraphy. This changed the therapeutic procedure in two of the five cases investigated so far.

Synthesis, characterization and biodistribution of neutral and lipid-soluble 99mTc-bisaminoethanethiol spiperone derivatives: Possible ligands for receptor imaging with SPECT

Using parts of the molecular structure of spiperone, two new ligand systems for complexation with [99mTc]technetium were prepared in order to develop potential receptor imaging agents for single photon emission computer tomography (SPECT). The bis-aminoethanethiols (BAT): 1-benzyl-4-(2-mercapto-2-methyl-4-aza-pentyl)-4-(2-mercapto-2-methyl- propylamino)-piperidine (benzylpiperidyl-BAT, BP-BAT) and 1-[3-(4-fluorobenzoyl)-propyl]-4-(2-mercapto-2-methyl-4-aza-pentyl)-4- (2-mercapto-2-methyl-propyl-amino)-piperidine (butyrophenoylpiperidyl-BAT, BUP-BAT) form stable, neutral and lipid soluble complexes with [99mTc]technetium at pH > or = 11 using SnCl2 as reducing agent in nearly quantitative radiochemical yields. Biodistribution of 99mTc-BP-BAT and 99mTc-BUP-BAT in rats showed a moderate clearance from blood and low uptake and retention in the liver, whereas brain uptake was moderate, however with prolonged brain retention. On the other hand, significant accumulations and retentions were observed in heart, kidney and lung with increasing oxygen/blood ratios up to 24 h. Within 24 h p.i. 22 and 29% of the injected dose (i.d.) of 99mTc-BP-BAT and 99mTc-BUP-BAT were eliminated by hepatobiliary excretion whereas 22% i.d. of both 99mTc-BAT complexes were excreted into the urine. Although first biodistribution studies of 99mTc-BP-BAT and 99mTc-BUP-BAT in rats showed relatively low brain uptake, the high uptake in peripheral, receptor rich organs indicates that compounds of this type may be used as a basis for further structural modification to develop agents with optimal properties for cerebral or peripheral receptor imaging with SPECT.

PET imaging with p-[I-124]iodo-l-phenylalanine as a new tool for diagnosis and postoperative control in patients with glioma.

Imaging protein metabolism by means of radiolabeled amino acids is an established method in the diagnosis of brain tumors. I-123 iodo-L-phenylalanine is a novel iodinated amino acid currently used for brain tumor imaging with single photon emission computed tomography. Radiolabeling of L-phenylalanine with iodine-124 allows in vivo studies of brain tumors by positron emission tomography, improving image quality. In this report, we evaluate the preand postoperative status in a 73-yearold patient with a glioma after one single injection of I-124 IPA using PET. A single administration of I-124 p-iodo-L-phenylalanine approved both an accurate diagnosis and a postoperative control in this same patient with a glioma.