Amino Acid Radiotracer Research Articles

Characterization of Large Brain Metastases with 18F-Fluciclovine PET/CT Treated with Staged Stereotactic Radiosurgery (SSRS): Phase 1 Proof-of-Concept Interim Analysis

Single-session stereotactic radiosurgery (SRS) for large brain metastases (>2cm) results in modest local control. Temporally staged SRS (SSRS), whereby 2 stages of SRS are delivered over a time interval of several weeks, is a novel strategy associated with improved control rates and acceptable radiation necrosis rates. Biomarkers for response are lacking. Here, we report interim results of a phase 1, proof-of-concept study (NCT04689048) to assess the potential clinical utility of amino acid radiotracer 18F-fluciclovine PET/CT as a functional integral biomarker for patients with large brain metastases treated with SSRS. Patients with previously untreated large brain metastases (≥1 lesion; >2cm) underwent a baseline (pre-treatment) 18F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI immediately before first SSRS (15 Gy), an interim PET/CT + MRI (4 weeks after the 1st SSRS, immediately prior the 2nd SSRS [15 Gy]), and post-treatment PET/CT + MRI (8 weeks after 2nd SSRS). This interim analysis reviewed the imaging characteristics from static PET images acquired 10-25 minutes after 18F-fluciclovine injection, for the first 7 enrolled patients who completed baseline imaging and 5 who completed the entire treatment course. Seven patients completed baseline imaging and were treated with SSRS for 9 protocol-eligible target lesions, and an additional 25 bystander lesions were treated with SRS. The median age was 72 years and 57% were female. All lesions > 5 mm exhibited baseline increased 18F-fluciclovine uptake compared to the normal contralateral brain. The median baseline target lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative reduction in diameter and volume were both 2% (-13% to 23% and -30% to 60%, respectively) at the interim scans, and at the first follow-up were 30% (-0.2% to 44%) and 43% (-13% to 94%), respectively. Corresponding median relative reduction values for SUVmax, SUVpeak, and SUVmean at interim scans were 20% (-174%-73%), 9% (-99% to 75%), and 14% (-36% to 69%), and at first follow-up 59% (21% to 87%), 41% (-11% to 86%), and 21% (-44% to 79%), respectively. Bystander lesions (< 2 cm) treated with SRS had a median baseline lesion diameter and volume of 0.5 cm (Range: 0.20-1.64 cm) and 0.06 cc (Range: 0.01-1.94 cc). Corresponding median reductions for SUVmax were 5% at interim and 63% at follow-up scans. This proof-of-concept interim study reports baseline 18F-fluciclovine metrics for patients with brain metastases of varying lesion diameters and volumes. Target lesions appear to demonstrate interval reduction in PET metrics after SSRS, more than dimensional measurements alone.

NEIM-02 CHARACTERIZATION OF LARGE BRAIN METASTASES WITH18F-FLUCICLOVINE PET/CT TREATED WITH STAGED STEREOTACTIC RADIOSURGERY (SSRS): INTERIM ANALYSIS OF A PILOT STUDY

Abstract We report the interim analysis of a phase 1, proof-of-concept study (NCT04689048), to assess the potential clinical utility of an amino acid radiotracer, 18F-fluciclovine PET/CT, as a functional integral biomarker for previously untreated patients with large brain metastases [BM] (≥1 lesion; &amp;gt;2cm) treated with staged stereotactic radiosurgery (SSRS). We reviewed the imaging characteristics from static PET images acquired 10-25 minutes after 18F-fluciclovine injection for the first seven enrolled patients (9 lesions) who completed baseline imaging, and five patients (7 lesions) who completed the treatment course (SSRS). Patients underwent a baseline (pre-treatment) 18F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI before 1st SSRS (15 Gy), repeated after 4 weeks (interim; before 2nd SSRS [15 Gy]), and 8 weeks after treatment completion (first follow-up after 2nd SSRS). The median age was 72 years and 57% were female. All lesions exhibited baseline increased 18F-fluciclovine uptake compared to normal contralateral brain. The median baseline lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative changes in diameter and volume were both -2% (-23% to +13% and -60% to +30%, respectively) at the interim scans, and -30% (-44% to +0.2%) and -43% (-94% to +13%), respectively, at first follow-up. Corresponding median relative changes values for SUVmax, SUVpeak, and SUVmean at interim scan were -20% (-73% to +174%), -9% (-75% to +99%), and -14% (-69% to +36%), and at first follow-up -59% (-87% to -21%), -41% (-86% to +11%), and -21% (-79% to +44%), respectively. In conclusion, this proof-of-concept interim study reports 18F-fluciclovine metrics for patients with large BMs, demonstrating interval reduction in PET metrics after SSRS, more than anatomical measurements alone, highlighting the potential of this as an imaging biomarker.

Disease Assessments in Patients with Glioblastoma.

The neuro-oncology team faces a unique challenge when assessing treatment response in patients diagnosed with glioblastoma. Magnetic resonance imaging (MRI) remains the standard imaging modality for measuring therapeutic response in both clinical practice and clinical trials. However, even for the neuroradiologist, MRI interpretations are not straightforward because of tumor heterogeneity, as evidenced by varying degrees of enhancement, infiltrating tumor patterns, cellular densities, and vasogenic edema. The situation is even more perplexing following therapy since treatment-related changes can mimic viable tumor. Additionally, antiangiogenic therapies can dramatically decrease contrast enhancement giving the false impression of decreasing tumor burden. Over the past few decades, several approaches have emerged to augment and improve visual interpretation of glioblastoma response to therapeutics. Herein, we summarize the state of the art for evaluating the response of glioblastoma to standard therapies and investigational agents as well as challenges and future directions for assessing treatment response in neuro-oncology. Monitoring glioblastoma responses to standard therapy and novel agents has been fraught with many challenges and limitations over the past decade. Excitingly, new promising methods are emerging to help address these challenges. Recently, the Response Assessment in Neuro-Oncology (RANO) working group proposed an updated response criteria (RANO 2.0) for the evaluation of all grades of glial tumors regardless of IDH status or therapies being evaluated. In addition, advanced neuroimaging techniques, such as histogram analysis, parametric response maps, morphometric segmentation, radio pharmacodynamics approaches, and the integrating of amino acid radiotracers in the tumor evaluation algorithm may help resolve equivocal lesion interpretations without operative intervention. Moreover, the introduction of other techniques, such as liquid biopsy and artificial intelligence could complement conventional visual assessment of glioblastoma response to therapies. Neuro-oncology has evolved over the past decade and has achieved significant milestones, including the establishment of new standards of care, emerging therapeutic options, and novel clinical, translational, and basic research. More recently, the integration of histopathology with molecular features for tumor classification has marked an important paradigm shift in brain tumor diagnosis. In a similar manner, treatment response monitoring in neuro-oncology has made considerable progress. While most techniques are still in their inception, there is an emerging body of evidence for clinical application. Further research will be critically important for the development of impactful breakthroughs in this area of the field.

The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review.

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the "Response Assessment in Neuro-Oncology" (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone.

P05.02.A 18F-FACBC PET/MRI in diagnostic assessment of gliomas

Abstract Background and Theory MRI and histopathological tissue sampling are routinely done as part of the diagnostic work-up of patients with glioma. MRI provides anatomical images with high resolution and excellent soft-tissue contrast. But this modality has limitations in identifying tumor grade, true tumor extension and differentiate viable tumor tissue from treatment induced changes. PET can provide quantitative information of cellular activity and metabolism, and may therefore have additional value compared to MRI alone. Objective The aim of this study was to find the sensitivity of [18F]FACBC PET in gliomas, and evaluate if PET imaging with this tracer can improve differentiation between low-and high-grade gliomas. Methods Patients with suspicion of primary (n=19) or recurrent gliomas (n=8) were recruited to this study from St. Olavs hospital, Trondheim University Hospital, Trondheim, and from the University Hospital of North Norway, Tromsø. PET acquisitions (30-45 min post injection) using the amino acid radiotracer [18F]FACBC (3 MBq/kg) were performed simultaneously to MRI acquisitions (T1 with and without contrast, FLAIR, and UTE for attenuation correction. The sensitivity of [18F]FACBC PET in glioma detection was assessed using histopathology as reference. Tumor-to-background ratios (TBRs) were compared to tumor subtype and grade to assess the diagnostic value of this tracer for glioma diagnostics. Results Histopathology revealed 2 WHO grade 1 gliomas (pilocytic astrocytoma n=1, pilocytic astrocytoma/ganglioglioma n=1), 7 WHO grade 2 gliomas(astrocytoma n=4, oligodendroglioma n=3), 7 WHO grade 3 gliomas(astrocytoma n=5, oligodendroglioma n=2) and 12 WHO grade 4 tumors(astrocytoma n=1, glioblastoma n=11). [18F]FACBC PET provided a sensitivity of 74.1% in the detection of gliomas. PET uptake was observed in all grade 4 tumors, 5/7 grade 3 tumors, 2/7 grade 2 tumors, and all grade 1 tumors. TBRpeak was high with a median value of 9.4 (range: 2.1-34.9) in PET positive tumors. Only tumors with a TBRpeak &amp;gt; 2.0 were detected with [18F]FACBC PET. TBRpeak was highest for grade 1 gliomas with a median value of 20.6, and increased significantly from grade 2 to grade 4 tumors with median values of 1.7 (grade 2), 6.2 (grade 3) and 12.4 (grade 4) (Kruskal-Wallis, p=0.001). Conclusion [18F]FACBC PET demonstrated high uptake in the majority of gliomas, and there was a clear tendency to higher uptake in the higher grade tumors. [18F]FACBC PET may be useful in the differentiation between glioms grades and subtypes. A future study using the same patient data will be performed to evaluate the assessment of [18F]FACBC PET in neurosurgical treatment planning. Image-localized biopsies from different regions of each tumor will be correlated to fused PET/MRI images to evaluate if [18F]FACBC PET can be used to guide surgical resection and to improve accuracy in histopathological tissue sampling.

Unconventional non-amino acidic PET radiotracers for molecular imaging in gliomas

The objective of this review was to explore the potential clinical application of unconventional non-amino acid PET radiopharmaceuticals in patients with gliomas. A comprehensive search strategy was used based on SCOPUS and PubMed databases using the following string: ("perfusion" OR "angiogenesis" OR "hypoxia" OR "neuroinflammation" OR proliferation OR invasiveness) AND ("brain tumor" OR "glioma") AND ("Positron Emission Tomography" OR PET). From all studies published in English, the most relevant articles were selected for this review, evaluating the mostly used PET radiopharmaceuticals in research centers, beyond amino acid radiotracers and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), for the assessment of different biological features, such as perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological characteristics in patients with glioma. At present, the use of non-amino acid PET radiopharmaceuticals specifically designed to assess perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological features in glioma is still limited. The use of investigational PET radiopharmaceuticals should be further explored considering their promising potential and studies specifically designed to validate these preliminary findings are needed. In the clinical scenario, advancements in the development of new PET radiopharmaceuticals and new imaging technologies (e.g., PET/MR and the application of the artificial intelligence to medical images) might contribute to improve the clinical translation of these novel radiotracers in the assessment of gliomas.

Comparison of amino acid radiotracers L-[methyl-&lt;sup&gt;11&lt;/sup&gt; C]methionine and &lt;i&gt;О&lt;/i&gt;-2-[&lt;sup&gt;18&lt;/sup&gt;F]fluoroethyl-L-tyrosine for PET/CT imaging of cerebral gliomas

Introduction. The radiotracer L-[methyl-11C]methionine (Met) has long been considered the tracer of choice in CNS tumors diagnosis using positron emission tomography, combined with computed tomography (PET/CT). However, there are more and more logistic arguments for the introduction of fluorinated amino acids into diagnostics, in particular, O-2-[18F]fluoroethyl-L-tyrosine (FET), for which our institute has developed its own method of radiochemical synthesis. The aim of the study was to compare amino acid radiotracers L-[methyl-11C]methionine (Met) and O-2-[18F]fluoroethyl-L-tyrosine (FET) in the imaging of cerebral gliomasusing PET/CT. Materials and methods. PET/CT studies using Met and FET were performed in 36 patients (15 men and 21 women) aged 28 to 73 years with suspected intracerebral tumor before surgery of biopsy. Pathohistologicalstudy verified gliomas(n-31) or other tumors (n=3), inflammatory process (n=2). The analysis of results included visual comparison of images, calculation of the tumor-to-brainratio (TBR) and metabolic tumor volume for Met and PET. Results. Visual and quantitative analysis of the scans revealed that tumor uptake pattern of FET was similar to those of Met. No significant differences were found in the TBR of both radiotracers in tumors of different grades of malignancy. A strong significant correlation (r=0,9) was revealed between the TBR of Met and FET in gliomas. There were no significant differences between tumor metabolic volumes when using the same cutoff values for both radiotracers. The ROC analysis established the same diagnostic value of Met and FET in differentiating low and high grade gliomas (area under curve 0,884 and 0,881, respectively). Conclusion. Amino acid radiotracers provide comparable diagnostic information in preoperative imaging of gliomas using PET/CT, which makes it possible to recommend FET as an adequate alternative to Met for PET centers without on-site cyclotron.

NIMG-02. 18F-FLUCICLOVINE PET/CT TO DISTINGUISH RADIATION NECROSIS FROM TUMOR PROGRESSION IN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY

Abstract PURPOSE/OBJECTIVE(S) To report descriptive updates of an ongoing pilot trial assessing whether 18F-Fluciclovine PET/CT, a widely available amino-acid radiotracer, is useful to distinguish radiation necrosis (RN) from tumor progression (TP) among patients with brain metastases. MATERIALS/METHODS The primary objective is to estimate the accuracy of 18F-Fluciclovine PET/CT in distinguishing RN from TP. We included adults with brain metastases who underwent prior stereotactic radiosurgery and presented with a follow-up MRI brain (with DSC-MR perfusion) which was equivocal for RN versus TP. Within 30 days of equivocal MRI, patients underwent 18F-Fluciclovine PET/CT on a Siemens Biograph mCT scanner with a 10 mCi bolus dose immediately prior to PET. PET data were collected in list-mode for 25 mins post-injection and were reconstructed as a static image of data 10-25 mins post-injection, and as a dynamic series of four 5-min frames between 5-25 mins post-injection. Quantitative metrics for each lesion were documented. Lesion to normal brain ratios were calculated. The reference standard was clinical follow-up with MRI brain (with DSC-MR perfusion) every 2-4 months until multidisciplinary consensus (or tissue confirmation) for diagnosis of RN versus TP. RESULTS From 7/2019-6/2020, 12 of 16 planned subjects with 17 lesions underwent 18F-Fluciclovine PET/CT. Primary histology was non-small cell lung cancer in 5 patients, breast in 4, melanoma in 2, and endometrial in 1. Among all 17 lesions, ranges of quantitative metrics were: SUVmax, 2.18-12.10; SUVmean, 1.16-7.37; SUVpeak, 1.06-4.45; normal brain SUVmean, 0.19-0.44; SUVmax/normal ratio, 7.50-45.40; SUVmean/normal ratio, 4.20-26.30; and SUVpeak/normal ratio, 3.90-26.40. Follow-up was completed for 5 patients (6 lesions). No adverse events have occurred. CONCLUSION In this population, 18F-Fluciclovine produces a wide range of lesion quantitative metric values and uniformly low uptake in normal brain, which may allow accurate discrimination. Ongoing additional accrual and follow up is required.

18F-Fluciclovine PET/CT to Distinguish Radiation Necrosis from Tumor Progression in Brain Metastases Treated with Stereotactic Radiosurgery

To assess whether 18F Fluciclovine PET CT, a widely available FDA approved amino acid radiotracer for suspected prostate cancer recurrence, is useful to distinguish radiation necrosis (RN) from tumor progression (TP) among patients with brain metastases treated with stereotactic radiosurgery (SRS). We report descriptive updates of an ongoing pilot clinical trial. The primary objective is to estimate the accuracy of 18F Fluciclovine PET CT in distinguishing RN from TP. We included adult patients with brain metastases who underwent prior SRS and presented with a follow up MRI brain (with DSC MR perfusion) which was equivocal for RN versus TP. Based on equivocal MRI and prior to PET, patients were grouped as equivocal but suspicious for either RN or TP, or truly equivocal, by the study neuroradiologist. Within 30 days of equivocal MRI brain, patients underwent 18F Fluciclovine PET CT on a Siemens Biograph mCT scanner with a 10 mCi bolus dose immediately prior to PET. PET data were collected in list mode for 25 mins post-injection and were reconstructed as a static image of data 10-25 mins post-injection, and as a dynamic series of four 5-min frames between 5 -25 mins post-injection. Quantitative metrics for each lesion were documented, including SUV max, SUV mean, SUV peak, and normal brain SUV mean. Lesion to normal brain ratios were calculated. The reference standard was clinical follow up with MRI brain (with DSC MR perfusion) every 2-4 months until multidisciplinary consensus (or tissue confirmation) for diagnosis of RN versus TP. From 7/2019-2/2020, 10 of 16 planned subjects enrolled, 2 patients withdrew consent, and 8 patients with 15 lesions underwent 18F Fluciclovine PET CT. Of the 8 imaged patients, primary histology was breast in 3, lung adenocarcinoma in 3, and melanoma in 2 patients. Among all 15 imaged lesions, ranges of quantitative metrics were: SUV max, 2.05-12.10; SUV mean, 1.14-7.37; SUV peak, 0.97-4.45; normal brain SUV mean, 0.19-0.35; SUV max/normal ratio, 6.9-43.2; SUV mean/normal ratio, 3.8-17.7; and SUV peak/normal ratio, 3.1-26.4. Follow up was completed for 4 pts (5 lesions) as described in the Table. No adverse events have been reported. In this population, 18F Fluciclovine produces a wide range of lesion quantitative metric values and low uptake in normal brain, which may allow accurate discrimination. Ongoing accrual and follow up is required to determine if 18F Fluciclovine is useful to distinguish RN from TP among patients with brain metastases treated with SRS.Abstract 3587; TableSubjectPrimaryFinal diagnosis (method)SUV maxSUV meanSUV peakNormal brain SUV meanSUV max/ normal ratioSUV mean/ normal ratioSUV peak/ normal ratio1MelanomaRN (biopsy)3.472.052.000.2712.77.57.32Lung AdenocarcinomaRN (biopsy)3.772.282.320.3211.67.07.23BreastTP (clinical follow up)7.784.432.700.3522.412.87.84BreastTP (clinical follow up)8.784.484.450.3525.312.912.84BreastTP (clinical follow up)12.17.372.560.2843.29.226.4 Open table in a new tab

MRI and PET/MRI in hematologic malignancies

The role of MRI differs considerably between the three main groups of hematological malignancies: lymphoma, leukemia, and myeloma. In myeloma, whole‐body MRI (WB‐MRI) is recognized as a highly sensitive test for the assessment of myeloma, and is also endorsed by clinical guidelines, especially for detection and staging. In lymphoma, WB‐MRI is presently not recommended, and merely serves as an alternative technique to the current standard imaging test, [18F]FDG‐PET/CT, especially in pediatric patients. Even for lymphomas with variable FDG avidity, such as extranodal mucosa‐associated lymphoid tissue lymphoma (MALT), contrast‐enhanced computed tomography (CT), but not WB‐MRI, is presently recommended, despite the high sensitivity of diffusion‐weighted MRI and its ability to capture treatment response that has been reported in the literature. In leukemia, neither MRI nor any other cross‐sectional imaging test (including positron emission tomography [PET]) is currently recommended outside of clinical trials. This review article discusses current clinical applications as well as the main research topics for MRI, as well as PET/MRI, in the field of hematological malignancies, with a focus on functional MRI techniques such as diffusion‐weighted imaging and dynamic contrast‐enhanced MRI, on the one hand, and novel, non‐FDG PET imaging probes such as the CXCR4 radiotracer [68Ga]Ga‐Pentixafor and the amino acid radiotracer [11C]methionine, on the other hand. Level of Evidence: 5 Technical Efficacy Stage: 3J. Magn. Reson. Imaging 2020;51:1325–1335.

Amino Acid PET Imaging of Glioma

Gliomas are among the most lethal malignancies in the world with dismal outcomes for high-grade tumors. These lesions are difficult to completely characterize with conventional magnetic resonance imaging and amino acid positron emission tomography is a rapidly progressing area of research with widespread clinical use. Amino acid positron emission tomography allows for more accurate glioma characterization compared to traditional imaging techniques including grading of disease, delineation of tumor spread, identification of recurrent disease, and prognosis. While the summarized radiotracers share some diagnostic properties, each also has its own weaknesses and strengths. This article summarizes recent developments and clinical applications of the most widely used amino acid radiotracers. While none of these agents are FDA approved in the United States, they are considered standard of care in Europe and other parts of the world with > 10,000 studies being performed in some centers (Langen et al. in J Neurooncol 120(3):665–666, 2014).

The Emerging Role of Amino Acid PET in Neuro-Oncology.

Imaging plays a critical role in the management of the highly complex and widely diverse central nervous system (CNS) malignancies in providing an accurate diagnosis, treatment planning, response assessment, prognosis, and surveillance. Contrast-enhanced magnetic resonance imaging (MRI) is the primary modality for CNS disease management due to its high contrast resolution, reasonable spatial resolution, and relatively low cost and risk. However, defining tumor response to radiation treatment and chemotherapy by contrast-enhanced MRI is often difficult due to various factors that can influence contrast agent distribution and perfusion, such as edema, necrosis, vascular alterations, and inflammation, leading to pseudoprogression and pseudoresponse assessments. Amino acid positron emission tomography (PET) is emerging as the method of resolving such equivocal lesion interpretations. Amino acid radiotracers can more specifically differentiate true tumor boundaries from equivocal lesions based on their specific and active uptake by the highly metabolic cellular component of CNS tumors. These therapy-induced metabolic changes detected by amino acid PET facilitate early treatment response assessments. Integrating amino acid PET in the management of CNS malignancies to complement MRI will significantly improve early therapy response assessment, treatment planning, and clinical trial design.

Addressing Chirality in the Structure and Synthesis of [18 F]5-Fluoroaminosuberic Acid ([18 F]FASu).

An increasing number of positron emission tomography (PET) radiotracers are being developed that are modelled on various amino acids to better understand disease in a manner that is complementary to traditional glycolysis-targeting [18 F]-fluorodeoxyglucose. Since chiral centers are ubiquitous in amino acids, generating an optically pure radiolabeled amino acid is important for patient dose, image quality and understanding the physiology behaviour. Past studies on the radiosynthesis of amino acid radiotracers seldom address the impact of reaction conditions on their chirality. The amino acid PET tracer, [18 F]5-fluoroaminosuberic acid ([18 F]FASu), has two chiral centers at the 2- and 5-positions and is being developed as a specific tracer for the cystine transporter (system xC- ), a biomarker for oxidative stress. Herein we report a method for synthesizing pure 2S,5R/S-FASu. We have resolved the 5-position configuration by applying Mosher's method combined with 2D NMR, which has enabled the synthesis of 18 FASu with fully known configuration. Our study serves as an example of a systematic method to identify and characterize amino acid tracers with chiral centers.

Diagnosis of Brain Tumors Using Amino Acid Transport PET Imaging with 18F-fluciclovine: A Comparative Study with L-methyl-11C-methionine PET Imaging.

Objective(s):18F-fluciclovine (trans-1-amino-3-[18F] fluorocyclobutanecarboxylic acid, [FACBC]) is an artificial amino acid radiotracer used for positron emission tomography (PET) studies, which is metabolically stable in vivo and has a long half-life. It has already been shown that FACBC-PET is useful for glioma imaging. However, there have been no reports evaluating the efficiency of FACBC-PET in the diagnosis of brain tumors in comparison with other PET tracers in clinical studies. The purpose of this study was to investigate the efficacy of FACBC-PET imaging in glioma diagnosis, compared to L-methyl-11C-methionine (MET)-PET.Methods:Six consecutive patients (four male, two female), who were clinically suspected of having high- or low-grade glioma, received both FACBC-PET and MET-PET within a two-week interval. T1-weighted, contrast-enhanced, T1-weighted, and fluid-attenuated inversion recovery magnetic resonance imaging was performed to assist with subsequent tissue resection. Visual findings and semi-quantitative analyses of FACBC and MET uptake, using standardized uptake values (SUVs) and lesion-to-contralateral normal brain tissue (LN) ratios, were evaluated to compare PET images.Results:SUVs for FACBC were lower than those for MET in the non-lesion cerebral cortex, brain stem, and cerebellar hemisphere. There was a weak positive correlation between FACBC and MET uptake in glioma tissue, although L/N ratios for FACBC were higher than those for MET in all the cases.Conclusion:FACBC-PET showed higher contrast than MET-PET by both visual and semi-quantitative analyses and may therefore provide better assessment for the detection of glioma. This study was registered as clinical trial (No. JapicCTI-132289).

Evaluation of Prostate Cancer with Radiolabeled Amino Acid Analogs.

Conventional imaging of prostate cancer has limitations related to the frequently indolent biology of the disease. PET is a functional imaging method that can exploit various aspects of tumor biology to enable greater detection of prostate cancer than can be provided by morphologic imaging alone. Radiotracers that are in use or under investigation for targeting salient features of prostate cancer include those directed to glucose, choline, acetate, prostate-specific membrane antigen, bombesin, and amino acids. The tumor imaging features of this last class of radiotracers mirror the upregulation of transmembrane amino acid transport that is necessary in carcinomas because of increased amino acid use for energy requirements and protein synthesis. Natural and synthetic amino acids radiolabeled for PET imaging have been investigated in prostate cancer patients. Early work with naturally occurring amino acid-derived radiotracers, such as l-11C-methionine and l-1-11C-5-hydroxytryptophan, demonstrated promising results, including greater sensitivity than 18F-FDG for intraprostatic and extraprostatic cancer detection. However, limitations with naturally occurring amino acid-derived compounds, including metabolism of the radiotracer itself, led to the development of synthetic amino acid radiotracers, which are not metabolized and therefore more accurately reflect transmembrane amino acid transport. Of the synthetic amino acid-derived PET radiotracers, anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC or 18F-fluciclovine) has undergone the most promising translation to human use, including the availability of simplified radiosynthesis. Several studies have indicated advantageous biodistribution in the abdomen and pelvis with little renal excretion and bladder activity-characteristics beneficial for prostate cancer imaging. Studies have demonstrated improved lesion detection and diagnostic performance of 18F-fluciclovine in comparison with conventional imaging, especially for recurrent prostate cancer, although issues with nonspecific uptake limit the potential role of 18F-fluciclovine in the diagnosis of primary prostate cancer. Although work is ongoing, recently published intrapatient comparisons of 18F-fluciclovine with 11C-choline reported higher overall diagnostic performance of the former, especially for the detection of disease relapse. This review is aimed at providing a detailed overview of amino acid-derived PET compounds that have been studied for use in prostate cancer imaging.

PET and SPECT studies in children with hemispheric low-grade gliomas

Molecular imaging is playing an increasing role in the pretreatment evaluation of low-grade gliomas. While glucose positron emission tomography (PET) can be helpful to differentiate low-grade from high-grade tumors, PET imaging with amino acid radiotracers has several advantages, such as better differentiation between tumors and non-tumorous lesions, optimized biopsy targeting, and improved detection of tumor recurrence. This review provides a brief overview of single-photon emission computed tomography (SPECT) studies followed by a more detailed review of the clinical applications of glucose and amino acid PET imaging in low-grade hemispheric gliomas. We discuss key differences in the performance of the most commonly utilized PET radiotracers and highlight the advantage of PET/MRI fusion to obtain optimal information about tumor extent, heterogeneity, and metabolism. Recent data also suggest that simultaneous acquisition of PET/MR images and the combination of advanced MRI techniques with quantitative PET can further improve the pretreatment and post-treatment evaluation of pediatric brain tumors.

High-Grade Glioma Management and Response Assessment—Recent Advances and Current Challenges

The management of high-grade gliomas (hggs) is complex and ever-evolving. The standard of care for the treatment of hggs consists of surgery, chemotherapy, and radiotherapy. However, treatment options are influenced by multiple factors such as patient age and performance status, extent of tumour resection, biomarker profile, and tumour histology and grade. Follow-up cranial magnetic resonance imaging (mri) to differentiate treatment response from treatment effect can be challenging and affects clinical decision-making. An assortment of advanced radiologic techniques-including perfusion imaging with dynamic susceptibility contrast mri, dynamic contrast-enhanced mri, diffusion-weighted imaging, proton spectroscopy, mri subtraction imaging, and amino acid radiotracer imaging-can now incorporate novel physiologic data, providing new methods to help characterize tumour progression, pseudoprogression, and pseudoresponse. In the present review, we provide an overview of current treatment options for hgg and summarize recent advances and challenges in imaging technology.

Abstract 5187: PET imaging of trastuzumab emtansine (T-DM1) drug delivery to intracranial patient derived xenograft (PDX) models of breast cancer metastasis

Abstract Background: It is estimated that 10-30% of all breast cancer patients at some point develop brain metastases. Overexpression of the human epidermal growth factor receptor 2 (HER2) is a independent risk factor for development of brain metastases. Up to 37% of patients with HER2-positive metastatic breast cancer develop brain metastases and half of these patients die as a result of failure to control the intracranial disease. A reason for this is the challenge to obtain efficient drug delivery across the blood brain barrier (BBB). Subcutaneous patient derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, when targeting brain tumors or metastases, the major impact of the BBB on drug bioavailability must be taken into consideration. Clinical PET imaging with 64Cu or 89Zr labeled trastuzumab has previously been able to visualize breast cancer brain metastases. The aim of our study was to investigate if PET imaging with 64Cu-labeled trastuzumab was predictive of the efficacy of trastuzumab emtansine (T-DM1) in a HER2 positive breast cancer PDX model established as an intracranial brain metastases model. Methods: The intracranial PDX model was established by stereotactic intracranial injection of enzymatically digested ST1339 tumor tissue. At confirmed tumor take, mice were randomized into two arms: control and T-DM1 (10 mg/kg/week x4). Treatment response was monitored by contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) and positron emission tomography (PET) with the amino acid radiotracer O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). PET/CT imaging with 64Cu-trastuzumab was performed in animals with confirmed intracranial ST1339 tumors prior to treatment with T-DM1 (10 mg/kg/week x4). Results: T-DM1 treatment with 10 mg/kg/week x4 of mice with intracranial tumors inhibited tumor growth and prolonged survival compared to non-treated animals. A variable response within the treatment group was observed. Forty percent had tumor shrinkage while 60% exhibited tumor growth within the duration of the therapy. The intracranial tumors were clearly visible on the 64Cu-trastuzumab PET images co-registered with T2-weighted MR images for anatomical localization. Interestingly, the intracranial tumor uptake between the animals was rather heterogeneous. Conclusion: A treatment response to T-DM1 was observed in an intracranial ST1339 HER2 positive breast cancer PDX model. PET imaging with 64Cu-trastuzumab confirmed delivery of trastuzumab to the tumors. Further quantitative image analysis of the intracranial 64Cu-trastuzumab tumor uptake will reveal if the drug delivery measured by 64Cu-trastuzumab PET imaging is predictive of the efficacy of T-DM1 in a HER2 positive PDX breast cancer brain metastases model. Citation Format: Carsten Haagen Nielsen, Mette K. Nedergaard, Lotte K. Kristensen, Camilla S. Knudsen, Michael J. Wick, Kyri Papadopoulos, Anthony Tolcher, Andreas Kjaer. PET imaging of trastuzumab emtansine (T-DM1) drug delivery to intracranial patient derived xenograft (PDX) models of breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5187.

Abstract P3-03-01: Intracranial PDX models of breast cancer metastasis

Abstract Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is an independent factor for development of brain metastases. Up to 37% of patients with HER2 positive disease relapse intracranially despite control of extra-cranial metastatic disease. Inability of anti-cancer agents to cross an intact blood-brain barrier (BBB) is a possible explanation for the increased incidence of brain metastases. Subcutaneous (SQ) patient-derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, orthotopic PDX models may confer a translational advantage as the patient tumor microenvironment is more closely mimicked. Especially when targeting brain tumors, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to develop a panel of intracranial PDX models of breast cancer brain metastases for pre-clinical efficacy studies of new anticancer drugs. Methods: SQ tumors from three different HER2 positive PDX breast cancer models designated ST340, ST1339 and ST1616B were enzymatically digested and used for intracranial stereotactic injection in nude mice. Contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) were used to determine tumor take. Intracranial tumor growth was monitored using MRI and positron emission tomography (PET) in conjunction with the amino acid radio tracer 18F-FET. Results: MRI confirmed tumor take in one model as early as 2 weeks after intracranial implantation. Increased 18F-FET uptake was detected in all models. MRI could be effectively used to monitor tumor growth and the corresponding 18F-FET PET images demonstrated increased 18F-FET uptake over time. Conclusion: Three different HER2 positive intracranial PDX breast metastases models were established from low passage SQ PDX models. We suggest, that using these intracranial PDX models of brain metastases, new drugs for advanced breast cancer can be evaluated in preclinical models that more closely mimic the microenvironment and the BBB in patients. In addition, translational imaging techniques can be evaluated during preclinical testing and the potential of tracers like 18F-FET as imaging biomarkers of therapeutic response can be assessed. Together, the established SQ and orthotopic PDX models of breast cancer and brain metastases can be used as a relevant translational platform for testing of new drugs. Citation Format: Nielsen CH, Nedergaard MK, Wick MJ, Papadopoulos K, Tolcher AW, Kjaer A. Intracranial PDX models of breast cancer metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-01.

Abstract A15: Efficacy of trastuzumab emtansine (T-DM1) in subcutaneous and intracranial patient derived xenograft models of breast cancer metastasis

Abstract Background: It is estimated that 10-30% of all breast cancer patients at some point develop brain metastases. Overexpression of the human epidermal growth factor receptor 2 (HER2) is a independent risk factor for development of brain metastases. Up to 37% of patients with HER2-positive metastatic breast cancer develop brain metastases and half of these patients die as a result of failure to control the intracranial disease. A reason for this is the challenge of efficient drug delivery across the blood brain barrier (BBB). Subcutaneous patient derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, when targeting brain tumors or metastases, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to compare the efficacy of trastuzumab emtansine (T-DM1) in a HER2 positive breast cancer PDX model established subcutaneously and as an intracranial brain metastases model. Methods: Mice were implanted subcutaneously with the HER2 positive breast cancer PDX model designated ST1339 and randomized into 3 treatment arms: Control, T-DM1 (5 mg/kg/week x4) and T-DM1 (10 mg/kg/week x4). Treatment response of subcutaneous tumors was monitored by caliper measurements. The intracranial PDX model was established by stereotactic intracranial injection of enzymatically digested ST1339 tumor tissue. At confirmed tumor take, mice were randomized into two arms: Control and T-DM1 (10 mg/kg/week x4). Treatment response was monitored by contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) and positron emission tomography (PET) with the amino acid radiotracer O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). Results: T-DM1 at 10 mg/kg/week x4 effectively inhibited tumor growth in the subcutaneous model whereas treatment with 5 mg/kg/week x4 did not have any effect on tumor growth. T-DM1 treatment at 10 mg/kg/week x4 of mice with intracranial tumors inhibited tumor growth and prolonged survival compared to non-treated animals. Conclusion: A treatment response to T-DM1 was observed in both the subcutaneous and intracranial ST1339 HER2 positive breast cancer PDX model. With the combination of subcutaneous and intracranial PDX models of breast cancer and breast cancer brain metastases new drugs can thus be tested in preclinical models that more closely mimic the microenvironment and the challenges of drug delivery across the BBB in patients. Citation Format: Carsten H. Nielsen, Mette K. Nedergaard, Lotte K. Kristensen, Camilla S. Knudsen, Michael J. Wick, Kyri Papadopoulos, Anthony W. Tolcher, Andreas Kjaer. Efficacy of trastuzumab emtansine (T-DM1) in subcutaneous and intracranial patient derived xenograft models of breast cancer metastasis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A15.