Fusion of [18F]FDG PET with Fluorescence Diffuse Optical Tomography to Improve Validation of Probes and Tumor Imaging

Purpose

Given the progress of fluorescence diffuse optical tomography (fDOT) technology, here, we study the additional benefits provided by multimodal PET/fDOT imaging by comparing the biodistribution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) in tumors with three fluorescent probes: a glucose analog, a protease activatable optical probe, and a ligand of αvβ3 integrin.

Procedures

Sequential fDOT/PET/computed tomography (CT) imaging of mice was performed with a custom multimodal mouse support that allows the subject to be transferred between the fDOT and the PET/CT scanners. Experiments were performed in xenografted tumor models derived from the human breast cancer line MDA-MB 231 and compared to ex vivo analysis.

Results

The three-dimensional signals showed that the fluorescent glucose analog is not colocalized with [¹⁸F]FDG, raising questions about its use as a surrogate probe of the PET tracer. Fusion of [¹⁸F]FDG with the other fluorescent probes showed evidence of high variability both for the protease activity and the αvβ3 integrin expression during tumor growth.

Conclusion

The added value of hybrid PET/fDOT over the two modalities was demonstrated for cross-validation of probes and for better characterization of tumor models.     

Preclinical Evaluation of a Novel c-Met Inhibitor in a Gastric Cancer Xenograft Model Using Small Animal PET

Purpose

Here, we describe the efficacy of the novel small molecule c-Met inhibitor BAY 853474 in reducing tumor growth in the Hs746T gastric cancer xenograft model and tested the suitability of 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) versus 3′-deoxy-3′-18F-fluorothymidine ([¹⁸F]FLT) for response monitoring in a gastric cancer xenograft mouse model using small animal PET.

Procedures

The c-Met inhibitor or vehicle control was administered orally at various doses in tumor-bearing mice. Glucose uptake and proliferation was measured using PET before, 48 and 96 h after the first treatment. The PET data were compared to data from tumor growth curves, autoradiography, Glut-1 and Ki-67 staining of tumor sections, and biochemical analysis of tissue probes, i.e., c-Met and ERK phosphorylation and cyclin D1 levels.

Results

BAY 853474 significantly reduces tumor growth. [¹⁸F]FDG uptake in Hs746T tumors was significantly reduced in the groups receiving the drug, compared with the control group. The [¹⁸F]FLT uptake in the tumor tissue was completely absent 96 h after treatment. Autoradiographic, immunohistochemical, and biochemical analyses confirmed the PET findings. Treatment with the c-Met inhibitor did not affect body weight or glucose levels, and no adverse effects were observed in the animals.

Conclusion

These preclinical findings suggest that clinical PET imaging is a useful tool for early response monitoring in clinical studies.     

Examining Changes in [18 F]FDG and [18 F]FLT Uptake in U87-MG Glioma Xenografts as Early Response Biomarkers to Treatment with the Dual mTOR1/2 Inhibitor AZD8055

Purpose

The mTOR kinase inhibitor AZD8055 inhibits both mTORC1 and mTORC2 leading to disruption of glucose metabolism and proliferation pathways. This study assessed the impact of single and multiple doses of AZD8055 on the uptake of the glucose metabolism marker 2-deoxy-2-[¹⁸?F]fluoro-d-glucose ([¹⁸?F]FDG) and the proliferation marker 3′-deoxy-3′-[¹⁸?F]fluorothymidine ([¹⁸?F]FLT) in U87-MG glioma xenografts.

Procedures

Mice bearing U87-MG tumours received either vehicle or AZD8055 (20 mg/kg) once daily p.o. Mice were imaged with either [¹⁸?F]FDG or [¹⁸?F]FLT PET to assess treatment response. Comparisons were made between in vivo imaging and ex vivo histopathology data.

Results

Tumour uptake of [¹⁸?F]FDG was reduced by 33 % 1 h after a single dose of AZD8055 and by 49 % following 4 days of dosing. These changes coincided with suppression of the mTOR pathway biomarkers pS6 and pAKT. In contrast, the effect of AZD8055 on [¹⁸?F]FLT uptake was inconsistent.

Conclusions

The very rapid change in [¹⁸?F]FDG uptake following acute AZD8055 treatment suggests that this could be used as an early mechanistic biomarker of metabolic changes resulting from mTOR inhibition. The utility of [¹⁸?F]FLT for measuring the anti-proliferative effect of AZD8055 remains unclear.     

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

Purpose

3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2??-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [¹⁸F]FLT in tumor xenografts.

Methods

The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[¹²⁵I]iodo-2??-deoxyuridine biodistribution measurements. In [¹⁸F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection. [¹⁸F]FLT biodistributions were measured 1 to 3 h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [¹⁸F]FDG tumor uptake. Using microPET, the dynamic distribution of [¹⁸F]FLT was followed for 1.5 h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation.

Results

FdUrd induced an immediate increase in tumor uptake of 5-[¹²⁵I]iodo-2??-deoxyuridine, that vanished after 6 h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [¹⁸F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [¹⁸F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [¹⁸F]FLT uptake in all tumors increased steadily up to 1.5 h. MRI showed a well-vascularized homogenous lymphoma with high [¹⁸F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis.

Conclusion

We showed a reliable and significant uptake increase of [¹⁸F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [¹⁸F]FLT PET.     

2-[18F]Fludarabine, a Novel Positron Emission Tomography (PET) Tracer for Imaging Lymphoma: a Micro-PET Study in Murine Models

Purpose

Fludarabine has proven to be of considerable efficacy in the treatment of low-grade lymphomas. We have developed the labeling of this drug with fluorine-18 and evaluated 2-[¹⁸F]fludarabine as a novel positron emission tomography (PET) probe for in vivo imaging.

Procedures

Preclinical studies were conducted with 2-[¹⁸F]fludarabine, in parallel with 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG), in Swiss CD-1 and CB17 severely combined immunodeficient (SCID) mice, both as tumor-free control groups, and SCID mice bearing RL lymphomas.

Results

In Swiss mice, micro-PET studies with 2-[¹⁸F]fludarabine showed a distribution restricted to the organs of excretion and the spleen, the latter being less evident in SCID animals. In lymphoma-bearing SCID mice, 2-[¹⁸F]fludarabine demonstrated a rapid tumor uptake over the first 20 min which subsequently plateaued and provided an improved contrast than that of [¹⁸F]FDG.

Conclusion

This radiotracer merits further evaluation to establish its clinical usefulness to image low-grade lymphoma in humans in future clinical investigations.     

Applying Amide Proton Transfer MR Imaging to Hybrid Brain PET/MR: Concordance with Gadolinium Enhancement and Added Value to [<Superscript>18</Superscript>F]FDG PET

Purpose

The purpose of this study is to evaluate the diagnostic concordance and metric correlations of amide proton transfer (APT) imaging with gadolinium-enhanced magnetic resonance imaging (MRI) and 2-deoxy-2-[¹⁸F-]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET), using hybrid brain PET/MRI.

Procedures

Twenty-one subjects underwent brain gadolinium-enhanced [¹⁸F]FDG PET/MRI prospectively. Imaging accuracy was compared between unenhanced MRI, MRI with enhancement, APT-weighted (APTW) images, and PET based on six diagnostic criteria. Among tumors, the McNemar test was further used for concordance assessment between gadolinium-enhanced imaging, APT imaging, and [¹⁸F]FDG PET. As well, the relation of metrics between APT imaging and PET was analyzed by the Pearson correlation analysis.

Results

APT imaging and gadolinium-enhanced MRI showed superior and similar diagnostic accuracy. APTW signal intensity and gadolinium enhancement were concordant in 19 tumors (100 %), while high [¹⁸F]FDG avidity was shown in only 12 (63.2 %). For the metrics from APT imaging and PET, there was significant correlation for 13 hypermetabolic tumors (P < 0.05) and no correlation for the remaining six [¹⁸F]FDG-avid tumors.

Conclusions

APT imaging can be used to increase diagnostic accuracy with no need to administer gadolinium chelates. APT imaging may provide an added value to [¹⁸F]FDG PET in the evaluation of tumor metabolic activity during brain PET/MR studies.

     

Evaluation of 2-Deoxy-2-[18F]Fluoro-D-glucose- and 3′-Deoxy-3′-[18F]Fluorothymidine–Positron Emission Tomography as Biomarkers of Therapy Response in Platinum-Resistant Ovarian Cancer

Purpose

We evaluated whether 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and 3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer.

Procedures

Paired platinum-sensitive and platinum-resistant ovarian cancer cells from the same patient, PEO1 and PEO4, grown as tumor xenografts in nude mice, were assessed by PET.

Results

The AKT inhibitor, API-2, resensitized platinum-resistant PEO4 tumors to cisplatin, leading to a markedly lower Ki67 labeling index (p????0.006, n?=?6 per group). [¹⁸F]FDG-PET and [¹⁸F]FLT-PET imaging variables were lower after combination treatment compared with vehicle treatment (p????0.006, n?=?6 per group). No changes were seen with either drug alone. PRAS40 phosphorylation status was a sensitive biochemical marker of pathway inhibition, whereas reductions thymidine kinase 1 expression defined the [¹⁸F]FLT response.

Conclusions

Therapeutic inhibition of AKT activation in acquired platinum-resistant disease can be imaged noninvasively by [¹⁸F]FDG-PET and [¹⁸F]FLT-PET warranting further assessment.     

Preclinical Imaging Evaluation of Novel TSPO-PET Ligand 2-(5,7-Diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1008) in Glioma

Purpose

Translocator protein (TSPO) concentrations are elevated in glioma, suggesting a role for TSPO positron emission tomography (PET) imaging in this setting. In preclinical PET studies, we evaluated a novel, high-affinity TSPO PET ligand, [¹⁸F]VUIIS1008, in healthy mice and glioma-bearing rats.

Procedures

Dynamic PET data were acquired simultaneously with [¹⁸F]VUIIS1008 injection, with binding reversibility and specificity evaluated in vivo by non-radioactive ligand displacement or blocking. Compartmental analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.

Results

[¹⁸F]VUIIS1008 exhibited rapid uptake in TSPO-rich organs. PET ligand uptake was displaceable with non-radioactive VUIIS1008 or PBR06 in mice. Tumor accumulation of [¹⁸F]VUIIS1008 was blocked by pretreatment with VUIIS1008 in rats. [¹⁸F]VUIIS1008 exhibited improved tumor-to-background ratio and higher binding potential in tumors compared to a structurally similar pyrazolopyrimidine TSPO ligand, [¹⁸F]DPA-714.

Conclusions

The PET ligand [¹⁸F]VUIIS1008 exhibits promising characteristics as a tracer for imaging glioma. Further translational studies appear warranted.     

Coupled Imaging with [<Superscript>18</Superscript>F]FBB and [<Superscript>18</Superscript>F]FDG in AD Subjects Show a Selective Association Between Amyloid Burden and Cortical Dysfunction in the Brain

Purpose

The present study was aimed to investigate the relationships between dysfunction of cortical glucose metabolism as detectable by means of 2-deoxy-2-[¹⁸F]fluoro -D-glucose ([¹⁸F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) and amyloid burden as detectable by means of 4-{(E)-2-[4-(2-{2-[2-[¹⁸F]fluoroethoxy]ethoxy}ethoxy)phenyl]vinyl}-N-methylaniline (florbetaben; [¹⁸F]FBB) in a group of patients affected by Alzheimer’s disease (AD).

Procedures

We examined 38 patients newly diagnosed with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a PET/CT scan using both [¹⁸F]FDG and [¹⁸F]FBB with an average interval of 1 month. We used statistical parametric mapping (SPM8) implemented in Matlab R2012b and WFU pickatlas for the definition of a region of interest (ROI) mask including the whole cortex. These data were then normalized on the counts of the cerebellum and then used for a regression analysis on [¹⁸F]FDG scans in SPM. Furthermore, 58 control subjects were used as control group for [¹⁸F]FDG PET/CT scans.

Results

SPM analysis in AD patients showed a significant negative correlation between [¹⁸F] FBB and [¹⁸F] FDG uptake in temporal and parietal lobes bilaterally. Of note, these areas in AD patients displayed a marked glucose hypometabolism compared to control group.

Conclusions

Combined imaging with [¹⁸F]FBB and [¹⁸FFDG shows that amyloid burden in the brain is related to cortical dysfunction of temporal and parietal lobes in AD.

     

Differences in Transport Mechanisms of trans-1-Amino-3-[18F]Fluorocyclobutanecarboxylic Acid in Inflammation,Prostate Cancer,and Glioma Cells: Comparison with l-[Methyl-11C]Methionine and 2-Deoxy-2-[18F]Fluoro-d-Glucose

Purpose

We aimed to elucidate trans-1-amino-3-[¹⁸F]fluorocyclobutanecarboxylic acid (anti-[¹⁸F]FACBC) uptake mechanisms in inflammatory and tumor cells, in comparison with those of l-[methyl-¹¹C]methionine ([¹¹C]Met) and 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG).

Procedures

Using carbon-14-labeled tracers, in vitro time-course, pH dependence, and competitive inhibition uptake experiments were performed in rat inflammatory (T cells, B cells, granulocytes, macrophages), prostate cancer (MLLB2), and glioma (C6) cells.

Results

Anti-[¹⁴C]FACBC uptake ratios of T/B cells to tumor cells were comparable, while those of granulocytes/macrophages to tumor cells were lower than those for [¹⁴C]FDG. Over half of anti-[¹⁴C]FACBC uptake by T/B and tumor cells was mediated by Na⁺-dependent amino acid transporters (system ASC), whereas most [¹⁴C]Met transport in all cells was mediated by Na⁺-independent carriers (system L).

Conclusions

The low anti-[¹⁸F]FACBC accumulation in granulocytes/macrophages may be advantageous in discriminating inflamed regions from tumors. The significant anti-[¹⁸F]FACBC uptake in T/B cells may cause false-positives in some cancer patients who undergo FACBC-positron emission tomography (PET).     

6-[18F]Fluoro-l-DOPA Uptake in the Rat Pancreas is Dependent on the Tracer Metabolism

Purpose

6-[¹⁸F]fluoro-l-3,4-dihydroxyphenyl alanine ([¹⁸F]FDOPA) positron emission tomography (PET) is a diagnostic tool which can detect malignancies of the pancreas. We aimed to study whether the manipulation of the [¹⁸F]FDOPA metabolic pathway would change the ¹⁸F-behavior to provide a biochemical foundation for PET imaging of rat pancreas with [¹⁸F]FDOPA.

Procedures

Inhibitors of aromatic amino acid decarboxylase, catechol-O-methyltransferase, monoamine oxidases A and B, or their combinations on [¹⁸F]FDOPA uptake, metabolism, and the regional distribution in the rat pancreas was evaluated using in vivo PET/computed tomography imaging, chromatographic metabolite analyses, and autoradiography.

Results

Enzyme inhibition generally increased the uptake of [¹⁸F]FDOPA derived ¹⁸F-radioactivity in rat pancreas. Dependent on which enzymatic pathway is blocked (or a combination of pathways), different radiolabeled metabolites in pancreas are responsible for this increase in uptake.

Conclusions

Altering the metabolism of [¹⁸F]FDOPA by using various enzymatic inhibitors increased the radioactivity uptake and changed the radiometabolic profile in the pancreas allowing better discrimination between pancreas and surrounding tissues of rat. However, these manipulations did not separate islets from the exocrine pancreas. Elucidating the metabolic behavior of [¹⁸F]FDOPA provides a biochemical foundation of PET imaging of the rat pancreas.     

PET Imaging of Stroke-Induced Neuroinflammation in Mice Using [18F]PBR06

Purpose

The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [¹⁸F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([¹⁸F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model.

Procedures

Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography.

Results

[¹⁸F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [¹⁸F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET.

Conclusions

[¹⁸F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.     

Evaluation of [18F]-CP18 as a PET Imaging Tracer for Apoptosis

Purpose

We identified and validated [¹⁸F]-CP18, a DEVD (the caspase 3 substrate recognition motif) containing substrate-based compound as an imaging tracer for caspase-3 activity in apoptotic cells.

Procedures

CP18 was radiolabeled with fluorine-18 using click chemistry. The affinity and selectivity of CP18 for caspase-3 were evaluated in vitro. The biodistribution and metabolism pattern of [¹⁸F]-CP18 were assessed in vivo. [¹⁸F]-CP18 positron emission tomography (PET) scans were performed in a dexamethasone-induced thymic apoptosis mouse model. After imaging, the mice were sacrificed, and individual organs were collected, measured in a gamma counter, and tested for caspase-3 activity.

Results

In vitro enzymatic caspase-3 assay demonstrated specific cleavage of CP18. In vivo, [¹⁸F]-CP18 is predominantly cleared through the kidneys and urine, and is rapidly eliminated from the bloodstream. There was a sixfold increase in caspase activity and a fourfold increase of [¹⁸F]-CP18 retention in the dexamethasone-induced thymus of treated versus control mice.

Conclusions

We report the use [¹⁸F]-CP18 as a PET tracer for imaging apoptosis. Our data support further development of this tracer for clinical PET applications.     

Comparison of 18F-labeled CXCR4 antagonist peptides for PET imaging of CXCR4 expression

Purpose

CXCR4 is overexpressed on tumor cells from many types of human cancers. A high level of CXCR4 expression often correlates with poor prognosis, chemotherapy resistance, and metastasis. The development of CXCR4-specific radiotracers for positron emission tomography (PET) imaging will allow in vivo evaluation of receptor expression level for diagnosis or therapeutic evaluation.

Procedures

Two new ¹⁸F-labeled radiotracers based on an Ac-TC14012 peptide, [¹⁸F]FP-Ac-TC14012 and [¹⁸F]FB-Ac-TC14012, were synthesized and characterized. The affinities of the 2-fluoropropionate (FP)-conjugated or 4-fluorobenzoate (FB)-conjugated peptides to CXCR4-transfected Chinese hamster ovarian (CHO) cells were evaluated in a competitive binding assay with [¹²⁵I]CXCL12 radioligand. The cell uptake and retention of [¹⁸F]FP-labeled and [¹⁸F]FB-labeled peptides were measured. The tumor targetability and pharmacokinetics of these two tracers were also evaluated by microPET imaging and biodistribution studies.

Results

The labeled peptides retained high binding affinity to CXCR4 and showed much higher uptake in CXCR4-positive CHO cells than in CXCR4-negative cells in vitro. The smaller and more hydrophilic [¹⁸F]FP prosthetic group resulted in higher affinity and lower nonspecific cell uptake compared to the [¹⁸F]FB-labeled peptide. Both radiotracers showed much higher accumulation in CXCR4-positive than CXCR4-negative tumor xenografts in mice and allowed clear visualization of CXCR4 expression by PET. Among the two, [¹⁸F]FP-Ac-TC14012 showed higher tumor uptake and better tumor-to-background contrast. Unlike their N-terminal 4-F-benzoate analogs, these two tracers had minimal blood retention, likely due to reduced red blood cell binding. Metabolic organs, such as the liver and kidney, also showed high uptake. When blocked with low-dose cold peptide (10 μg), the tumor uptake was significantly increased, most likely due to the increased concentration in blood circulation, as evidenced by decreased liver uptake.

Conclusion

These results demonstrate that the [¹⁸F]FP-labeled Ac-TC14012 peptide with high tumor uptake, low nonspecific binding, and good tumor-to-background contrast promises [¹⁸F]FP-Ac-TC14012 as a PET tracer for in vivo PET imaging of CXCR4 expression.     

Dynamic Changes of FDG Uptake and Clearance in Normal Tissues

Purpose

This study aims to evaluate dynamic 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake in normal tissues.

Procedures

Thirty male patients underwent FDG positron emission tomography (PET)/computed tomography imaging at 1, 2, and 3 h after tracer injection. Standardized uptake values (SUV) were obtained in regions of interest of normal tissues.

Results

The aorta (blood pool), liver, and spleen FDG activity demonstrated significantly and continuously decreased activity from 1 to 2 and 2 to 3 h, while FDG uptake in the lungs, pancreas, lymph nodes, and skeletal muscle decreased from 1 to 2 h only. In contrast, the left ventricular myocardium demonstrated two patterns of dynamic changes: myocardium with higher FDG uptake (SUV_max?≥?3.25) on the initial images had more remarkable increased activity on the delayed images, while myocardium with lower FDG uptake (SUV_max?<?3.25) on the initial imaging had no increased uptake on delayed imaging. Increased FDG uptake was also observed in the bones on the delayed images. No significant changes of FDG uptake were noted in the parotid gland, thyroid gland, and prostate gland.

Conclusions

These findings may help nuclear medicine physicians when comparing images performed at different time points, when using FDG uptake in internal reference regions as a relative indicator of FDG uptake in a specific lesion, and when reading a delayed FDG PET imaging.     

Positron Emission Tomography with [18F]-3′-Deoxy-3′fluorothymidine (FLT) as a Predictor of Outcome in Patients with Locally Advanced Resectable Rectal Cancer: a Pilot Study

Purpose

This pilot study was performed to evaluate whether tumor uptake of ¹⁸F-labeled 3′-deoxy-3′fluorothymidine (FLT), a proliferative radiotracer, at baseline and early during therapy, is predictive of outcome in locally advanced rectal cancer.

Procedures

Fourteen patients underwent positron emission tomography (PET) with 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) and FLT before therapy and PET with FLT approximately 2 weeks after initiating neoadjuvant chemoradiotherapy. FLT and FDG uptake were evaluated qualitatively and by maximum standardized uptake value (SUV_max). Tumor FLT and FDG uptake were correlated with disease-free survival (DFS).

Results

Thirteen patients underwent surgery after therapy, one died before surgery with progressive disease. FDG-PET/computed tomography detected regional lymph node metastases in five and FLT-PET was positive in one. High pretherapy FDG uptake (SUV_max?≥?14.3), low during-therapy FLT uptake (SUV_max?<?2.2), and high percentage change in FLT uptake (≥60 %) were predictive of improved DFS (p?<?0.05 for all three values).

Conclusion

Pretherapy FDG uptake, during-therapy FLT uptake, and percentage change in FLT uptake were equally predictive of DFS.     

Electrophilic Addition of Chlorine Monofluoride for PET tracers

Purpose

We have studied the utility of [¹⁸F]ClF electrophilic addition to the carbon–carbon double bond of analogues of a model positron emission tomography (PET) tracer, [¹⁸F]EF5. The consequence of simultaneous chlorine/fluorine addition on lipophilicity and biological activity of the molecule is evaluated.

Procedures

Post-target produced [¹⁸F]F₂ was reacted with Cl₂ to produce [¹⁸F]ClF, which was used in electrophilic addition.

Results

[¹⁸F]ClF was produced and used to label chlorinated analogues of [¹⁸F]EF5. The chlorinated analogues, [¹⁸F]EF4Cl_a and [¹⁸F]EF4Cl_b, were synthesized simultaneously. The in vivo uptake of the analogues compared well with [¹⁸F]EF5 uptake in tumor-bearing mice.

Conclusion

[¹⁸F]ClF is a suitable labeling reagent for electrophilic addition to double bonds of PET tracers. The results show that the modification of the pentafluoro group of [¹⁸F]EF5 by monofluorine-for-chlorine exchange affected the lipophilicity, but the hypoxia avidity of these molecules was not apparently altered.     

Suitability of [18F]Altanserin and PET to Determine 5-HT2A Receptor Availability in the Rat Brain: In Vivo and In Vitro Validation of Invasive and Non-Invasive Kinetic Models

Purpose

While the selective 5-hydroxytryptamine type 2a receptor (5-HT_2AR) radiotracer [¹⁸F]altanserin is well established in humans, the present study evaluated its suitability for quantifying cerebral 5-HT_2ARs with positron emission tomography (PET) in albino rats.

Procedures

Ten Sprague Dawley rats underwent 180 min PET scans with arterial blood sampling. Reference tissue methods were evaluated on the basis of invasive kinetic models with metabolite-corrected arterial input functions. In vivo 5-HT_2AR quantification with PET was validated by in vitro autoradiographic saturation experiments in the same animals.

Result

Overall brain uptake of [¹⁸F]altanserin was reliably quantified by invasive and non-invasive models with the cerebellum as reference region shown by linear correlation of outcome parameters. Unlike in humans, no lipophilic metabolites occurred so that brain activity derived solely from parent compound. PET data correlated very well with in vitro autoradiographic data of the same animals.

Conclusion

[¹⁸F]Altanserin PET is a reliable tool for in vivo quantification of 5-HT_2AR availability in albino rats. Models based on both blood input and reference tissue describe radiotracer kinetics adequately. Low cerebral tracer uptake might, however, cause restrictions in experimental usage.     

CD80 Is Upregulated in a Mouse Model with Shear Stress-Induced Atherosclerosis and Allows for Evaluating CD80-Targeting PET Tracers

Purpose

A shear stress-induced atherosclerosis mouse model was characterized for its expression of inflammation markers with focus on CD80. With this model, we evaluated two positron emission tomography (PET) radiotracers targeting CD80 as well as 2-deoxy-2-[¹⁸F]fluoro-d-mannose ([¹⁸F]FDM) in comparison with 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG).

Procedure

A flow constrictive cuff implanted around the common carotid artery in apolipoprotein E knockout mice resulted in plaque formation. CD80 expression levels and plaque histopathology were evaluated. Serial PET/X-ray computed tomography scans were performed to follow inflammation.

Results

Plaque formation with increased levels of CD80 was observed. Histologically, plaques presented macrophage-rich and large necrotic areas covered by a thin fibrous cap. Of the CD80-specific tracers, one displayed an increased uptake in plaques by PET. Both [¹⁸F]FDG and [¹⁸F]FDM accumulated in atherosclerotic plaques.

Conclusion

This mouse model presented, similar to humans, an increased expression of CD80 which renders it suitable for non-invasively targeting CD80-positive immune cells and evaluating CD80-specific radiotracers.