False Positive Findings of [18F]PSMA-1007 PET/CT in Patients After Radical Prostatectomy with Undetectable Serum PSA Levels.

Background: PET-CT using prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals labeled with 68Ga or 18F has emerged as the most sensitive staging tool in prostate cancer (PC). Nonetheless, the occurrence of false positive (FP) findings presents a major concern of this approach. In this prospective study, we investigated the frequency and pattern of false-positive findings of [18F]PSMA-1007 PET/CT in patients after radical prostatectomy with undetectable serum PSA levels. Any discrete non-physiological accumulation of [18F]PSMA-1007 in this population is by definition FP. Methods: Seventeen men after radical prostatectomy, whose serum PSA levels were <0.05 ng/mL at 2-24 months after surgery were prospectively recruited. PET/CT was acquired at both 1 and 2 h after injection of [18F]PSMA-1007. Findings: Three studies (18%) were interpreted as completely normal. Thirty-five foci of "non-physiological" uptake were observed in the remaining 14 (82%) patients, including a single skeletal focus in four patients, multiple skeletal foci in five patients and soft tissue uptake in eight, including in a desmoid tumor and in pelvic lymphocele. The SUVmax of all lesions was in the range of 1-7, except for the desmoid tumor which measured 12.7. All foci were visible in both the 1- and the 2 h studies, presenting a minor (<10%), statistically insignificant increase of SUVmax during this time-interval. Interpretation: FP [18F]PSMA-1007-avid foci are found in about 80% of patients with undetectable serum PSA levels. Thus, focal uptake of [18F]PSMA-1007 outside its physiological distribution is not a categorical sign of metastasis and can arise from non-specific uptake of the ligand. The interpretation of [18F]PSMA-1007 PET/CT studies should always consider the clinical context, and lesions with SUVmax < 7 are suspicious for FP.

Organic Cation Transporter-Mediated Accumulation of Quinolinium Salts in the LV Myocardium of Rodents.

PURPOSE: Quaternary ammonium salts have demonstrated marked accumulation in the left ventricular (LV) myocardium of rodents and swine. To investigate the mechanism underlying this uptake, the present study examined the interaction of [18F]fluoroethylquinolinium ([18F]FEtQ) with the family of organic cation transporters (OCTs). PROCEDURES: The cellular uptake of [18F]FEtQ into HEK293 cells, expressing human OCT1, -2, or -3 (HEK293-hOCT), and its inhibition by corticosterone was evaluated in vitro. The inhibitory effect of decynium 22 (D 22) in vivo was also studied, using PET/CT of HEK293-hOCT tumor-bearing mice. Furthermore, the distribution kinetics of [18F]FEtQ were determined in rats, with and without pre-administration of corticosterone, and following administration to a non-human primate (NHP). RESULTS: The accumulation of [18F]FEtQ in HEK293-hOCT cells was 15-20-fold higher than in control cells and could be inhibited by corticosterone. in vivo, the uptake of [18F]FEtQ in the LV myocardium of corticosterone-treated rats was significantly reduced compared to that of untreated animals. Similarly, following administration of D 22 to HEK293-hOCT tumor-bearing mice, the peak tumor uptake of [18F]FEtQ was reduced by 40-45 % compared to baseline. Contrary to the distinct accumulation of [18F]FEtQ in the LV myocardium of rats, no cardiac uptake was observed following its administration to a NHP. CONCLUSIONS: The quinolinium salt derivative [18F]FEtQ interacts with the family of OCTs, and this interaction could account, at least in part, for the increased uptake in the LV myocardium of rodents. Nonetheless, its low affinity for hOCT3 and the results of PET/CT imaging in a NHP indicate a limited clinical applicability as a radiopharmaceutical for cardiac and/or OCT imaging.

Head-to-head comparison of [68Ga]Ga-FAPI-04 and [18F]-FDG PET/CT in evaluating the extent of disease in gastric adenocarcinoma.

BACKGROUND: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) may sometimes be suboptimal for imaging gastric adenocarcinoma. The recently introduced [68Ga]Ga-FAPI-04 (FAPI) PET/CT targets tumor stroma and has shown considerable potential in evaluating the extent of disease in a variety of tumors. METHODS: We performed a head-to-head prospective comparison of FAPI and FDG PET/CT in the same group of 13 patients with gastric adenocarcinoma who presented for either initial staging (n = 10) or restaging (n = 3) of disease. Lesion detection and maximum standardized uptake value (SUVmax) were compared between the two types of radiotracers. RESULTS: All ten primary gastric tumors were FAPI-positive (100% detection rate), whereas only five were also FDG-positive (50%). SUVmax was not significantly different, but the tumor-to-background ratio was higher for FAPI (mean, median, and range of 4.5, 3.2, and 0.8-9.7 for FDG and 12.9, 11.9, and 2.2-23.9 for FAPI, P = 0.007). The level of detection of regional lymph node involvement was comparable. FAPI showed a superior detection rate for peritoneal carcinomatosis (100% vs. none). Two patients with widespread peritoneal carcinomatosis underwent a follow-up FAPI scan after chemotherapy: one showed partial remission and the other showed progressive disease. CONCLUSIONS: The findings of this pilot study suggest that FAPI PET/CT outperforms FDG PET/CT in detecting both primary gastric adenocarcinoma and peritoneal carcinomatosis from gastric cancer. FAPI PET/CT also shows promise for monitoring response to treatment in patients with peritoneal carcinomatosis from gastric cancer; however, larger trials are needed to validate these preliminary findings.

Development and preclinical evaluation of novel fluorinated ammonium salts for PET myocardial perfusion imaging.

We previously presented the radiolabeled ammonium salt [11C]-dimethyl diphenylammonium trifluoromethanesulfonate ([11C]DMDPA) as a potential novel PET-MPI agent. The current study aimed to increase the clinical applicability of PET-MPI by designing and synthesizing fluorinated ammonium salt derivatives. Four fluorinated DMDPA derivatives and two quinolinium salt analogs were radiolabeled. The dynamic distribution in vivo, following injection of each derivative into male SD rats, was evaluated using small-animal dedicated PET/CT. Organ uptake after injection of [18F]fluoroethylquinolinium acetate ([18F]FEtQ) was examined ex vivo. Four fluorinated DMDPA derivatives were synthesized, two were labeled with fluorine-18: [18F]fluoroethyl-methyldiphenylammonium trifluoromethanesulfonate ([18F]FEMDPA) and [18F]fluorobuthyl-methyldiphenylammonium trifluoromethanesulfonate ([18F]FBMDPA). The other two were labeled using carbon-11: [11C]methyl-(3-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([11C]3-F-DMDPA) and [11C]methyl-(4-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([11C]4-F-DMDPA). All four DMDPA derivatives exhibited significantly lower heart/liver radioactivity uptake ratios (0.6, 0.4, 0.7 and 0.6, respectively) compared to that of [11C]DMDPA (1.2). Conversely, the two radiolabeled quinolinium salt derivatives, [11C]methylquinolinium iodide ([11C]MeQ) and [18F]FEtQ demonstrated improved heart/liver ratios (2.0 and 1.3, respectively) with clear visualization of the left ventricle myocardium. Renal clearance was the major route of elimination. Among the fluorinated quaternary ammonium salts tested, [18F]FEtQ yielded the best images. Further studies are in progress to elucidate the underlying mechanism of its cardiac uptake.

[18F]-FDHT PET/CT as a tool for imaging androgen receptor expression in high-grade glioma.

BACKGROUND: G lioblastoma (GBM) is associated with poor overall survival. Recently, we showed that androgen receptor (AR) protein is overexpressed in 56% of GBM specimens and AR antagonists induced dose-dependent death in several GBM cell lines and significantly reduced tumor growth and prolonged the lifespan of mice implanted with human GBM. 16ß-18F-fluoro-5α-dihydrotestosterone ([18F]-FDHT) is a positron emission tomography (PET) tracer used to detect AR expression in prostate and breast cancers. This study was aimed at exploring the ability of [18F]-FDHT-PET to detect AR expression in high-grade gliomas. METHODS: Twelve patients with suspected high-grade glioma underwent a regular workup and additional dynamic and static [18F]-FDHT-PET/CT. Visual and quantitative analyses of [18 F]-FDHT kinetics in the tumor and normal brain were performed. Mean and maximum (max) standardized uptake values (SUVs) were determined in selected volumes of interest. The patients had surgery or biopsy after PET/CT. AR protein was analyzed in the tumor samples by western blot. Fold change in AR expression was calculated by densitometry analysis. Correlation between imaging and AR protein samples was determined. RESULTS: In six of the 12 patients, [18 F]-FDHT uptake was significantly higher in the tumor than in the normal brain. These patients also had increased AR protein expression within the tumor. Pearson correlation coefficient analysis for the tumor-to-control normal brain uptake ratio in terms of SUVmean versus AR protein expression was positive and significant (R = 0.84; P = .002). CONCLUSION: [18 F]-FDHT-PET/CT could identify increased AR expression in high-grade glioma.

Head-to-Head Comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and Immunohistochemical Analysis as a Reference Standard.

18F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)-based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of 18F-PSMA-1007 with 68Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate- or high-risk PCa. Methods: Sixteen patients with intermediate- or high-risk PCa underwent 18F-PSMA-1007 and 68Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen κ-coefficient was used to assess the concordance between 18F-PSMA-1007 and 68Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUVmax was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers (κ ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with 18F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both 18F-PSMA-1007 and 68Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediate- or high-risk PCa at staging. 18F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance.

Fine-tuning of the automated [18 F]PSMA-1007 radiosynthesis.

Radiolabeled prostate-specific membrane antigen (PSMA) targeting PET-tracers have become desirable radiopharmaceuticals for the imaging of prostate cancer (PC). Recently, the PET radiotracer [18 F]PSMA-1007 was introduced as an alternative to [68 Ga]Ga-PSMA-11, for staging and diagnosing biochemically recurrent PC. We incorporated a one-step procedure for [18 F]PSMA-1007 radiosynthesis, using both Synthra RNplus and GE TRACERlab FxFN automated modules, in accordance with the recently described radiolabeling procedure. Although the adapted [18 F]PSMA-1007 synthesis resulted in repeatable radiochemical yields (55 ± 5%, NDC), suboptimal radiochemical purities of 87 ± 8% were obtained using both modules. As described here, modifications made to the radiolabeling and the solid-phase extraction purification steps reduced synthesis time to 32 minutes and improved radiochemical purity to 96.10%, using both modules, without shearing the radiochemical yield.

Development of a Fluorinated Analogue of Erlotinib for PET Imaging of EGFR Mutation-Positive NSCLC.

PURPOSE: Positron emission tomography (PET) using [11C]erlotinib identifies non-small cell lung carcinoma (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFRm). The short half-life of C-11, however, limits its clinical utility to centers with a nearby cyclotron. We therefore developed a F-18-labeled analogue of erlotinib for imaging EGFRm NSCLC. PROCEDURES: 6-O-Fluoroethylerlotinib (6-O-FEE) was synthesized and its anti-proliferative activity was tested using human NSCLC cell lines. The F-18-labeled compound, 6-O-[18F]FEE, was obtained in a two-step synthesis, and PET acquisitions were carried out following its injection to NSCLC tumor-bearing mice. RESULTS: In vitro, 6-O-FEE had maintained the selectivity and potency of erlotinib to EGFRm NSCLC. In vivo, 6-O-[18F]FEE accumulation in EGFRm tumors at 60 min after injection was 2- and 3.3-fold higher than in erlotinib-resistant or erlotinib-insensitive tumors, respectively. CONCLUSIONS: 6-O-[18F]FEE holds promise for imaging EGFRm NSCLC, warranting further investigation to fully explore its potential for stratifying NSCLC patients.

68Ga-PSMA is a novel PET-CT tracer for imaging of hepatocellular carcinoma: A prospective pilot study.

Background:68Ga-Prostate Specific Membrane Antigen (68Ga-PSMA), a positron emission tomography (PET) tracer that was recently introduce for imaging of prostate cancer, may accumulate in other solid tumors including Hepatocellular Carcinoma (HCC). The aim of the study was to assess the potential role of 68Ga-PSMA PET-Computed Tomography (CT) for imaging of HCC. Material and Methods: A prospective pilot study in seven patients with HCC with 41 liver lesions: 37 suspected malignant lesions (tumor lesions) and 4 regenerative nodules. For each liver lesion, uptake of 68Ga-PSMA and 18F-FDG uptake were measured [standard uptake value (SUV) and lesion-to-liver background ratios (TBR-SUV)], and correlated with dynamic characteristics (HU and TBR-HU) obtained on contrast enhanced CT data. Immunohistochemistry staining of PSMA in the tumor tissue was analyzed in samples obtained from 5 patients with HCC and compared to control samples from 3 patients with prostate cancer. Results: Thirty-six of the 37 tumor lesions and none of the regenerative nodules showed increased 68Ga-PSMA uptake while only 10 lesions were 18F-FDG avid. Based on contrast enhancement, tumor lesions were categorized into 27 homogeneously enhancing lesions, nine lesions with "mosaic" enhancement composed of enhancing and non-enhancing regions in the same lesion and a single non-enhancing lesion, the latter being the only non-68Ga-PSMA avid lesion. Using the Mann-Whitney test, 68Ga-PSMA uptake was found significantly higher in enhancing tumor areas compared to non-enhancing areas and in contrast, 18F-FDG uptake was higher in non-enhancing areas, P<0.001 for both. 68Ga-PSMA uptake (TBR SUVmax) was found to correlate with vascularity (TBR-HU) (Spearman r=0.866, p<0.001). Immunohistochemistry showed intense intra-tumoral microvessel staining for PSMA in HCC, in contrast with cytoplasmic and membranous staining, mainly in the luminal border, in prostate cancer samples. In two of the study patients 68Ga-PSMA PET-CT identified unexpected extrahepatic metastases. Four regenerative liver nodules showed no increased uptake of either of the PET tracers. Conclusion:68Ga-PSMA PET-CT is superior to 18F-FDG PET-CT in imaging patients with HCC. HCC lesions are more commonly hypervascular taking up 68Ga-PSMA in tumoral micro-vessels. 68Ga-PSMA PET-CT is a potential novel modality for imaging patients with HCC.

Comprehensive Auditing in Nuclear Medicine Through the International Atomic Energy Agency Quality Management Audits in Nuclear Medicine (QUANUM) Program. Part 1: the QUANUM Program and Methodology.

An effective management system that integrates quality management is essential for a modern nuclear medicine practice. The Nuclear Medicine and Diagnostic Imaging Section of the International Atomic Energy Agency (IAEA) has the mission of supporting nuclear medicine practice in low- and middle-income countries and of helping them introduce it in their health-care system, when not yet present. The experience gathered over several years has shown diversified levels of development and varying degrees of quality of practice, among others because of limited professional networking and limited or no opportunities for exchange of experiences. Those findings triggered the development of a program named Quality Management Audits in Nuclear Medicine (QUANUM), aimed at improving the standards of NM practice in low- and middle-income countries to internationally accepted standards through the introduction of a culture of quality management and systematic auditing programs. QUANUM takes into account the diversity of nuclear medicine services around the world and multidisciplinary contributions to the practice. Those contributions include clinical, technical, radiopharmaceutical, and medical physics procedures. Aspects of radiation safety and patient protection are also integral to the process. Such an approach ensures consistency in providing safe services of superior quality to patients. The level of conformance is assessed using standards based on publications of the IAEA and the International Commission on Radiological Protection, and guidelines from scientific societies such as Society of Nuclear Medicine and Molecular Imaging (SNMMI) and European Association of Nuclear Medicine (EANM). Following QUANUM guidelines and by means of a specific assessment tool developed by the IAEA, auditors, both internal and external, will be able to evaluate the level of conformance. Nonconformances will then be prioritized and recommendations will be provided during an exit briefing. The same tool could then be applied to assess any improvement after corrective actions are taken. This is the first comprehensive audit program in nuclear medicine that helps evaluate managerial aspects, safety of patients and workers, clinical practice, and radiopharmacy, and, above all, keeps them under control all together, with the intention of continuous improvement.

Comprehensive Auditing in Nuclear Medicine Through the International Atomic Energy Agency Quality Management Audits in Nuclear Medicine Program. Part 2: Analysis of Results.

The International Atomic Energy Agency has developed a program, named Quality Management Audits in Nuclear Medicine (QUANUM), to help its Member States to check the status of their nuclear medicine practices and their adherence to international reference standards, covering all aspects of nuclear medicine, including quality assurance/quality control of instrumentation, radiopharmacy (further subdivided into levels 1, 2, and 3, according to complexity of work), radiation safety, clinical applications, as well as managerial aspects. The QUANUM program is based on both internal and external audits and, with specifically developed Excel spreadsheets, it helps assess the level of conformance (LoC) to those previously defined quality standards. According to their level of implementation, the level of conformance to requested standards; 0 (absent) up to 4 (full conformance). Items scored 0, 1, and 2 are considered non-conformance; items scored 3 and 4 are considered conformance. To assess results of the audit missions performed worldwide over the last 8 years, a retrospective analysis has been run on reports from a total of 42 audit missions in 39 centers, three of which had been re-audited. The analysis of all audit reports has shown an overall LoC of 73.9 ± 8.3% (mean ± standard deviation), ranging between 56.6% and 87.9%. The highest LoC has been found in the area of clinical services (83.7% for imaging and 87.9% for therapy), whereas the lowest levels have been found for Radiopharmacy Level 2 (56.6%); Computer Systems and Data Handling (66.6%); and Evaluation of the Quality Management System (67.6%). Prioritization of non-conformances produced a total of 1687 recommendations in the final audit report. Depending on the impact on safety and daily clinical activities, they were further classified as critical (requiring immediate action; n = 276; 16% of the total); major (requiring action in relatively short time, typically from 3 to 6 months; n = 604; 36%); whereas the remaining 807 (48%) were classified as minor, that is, to be addressed whenever possible. The greatest proportion of recommendations has been found in the category "Managerial, Organization and Documentation" (26%); "Staff Radiation Protection and Safety" (17.3%); "Radiopharmaceuticals Preparation, Dispensing and Handling" (15.8%); and "Quality Assurance/Quality Control" and "Management of Equipment and Software" (11.4%). The lowest level of recommendations belongs to the item "Human Resources" (4%). The QUANUM program proved applicable to a wide variety of institutions, from small practices to larger centers with PET/CT and cyclotrons. Clinical services rendered to patients showed a good compliance with international standards, whereas issues related to radiation protection of both staff and patients will require a higher degree of attention. This is a relevant feedback for the International Atomic Energy Agency with regard to the effective translation of safety recommendations into routine practice. Training on drafting and application of standard operating procedures should also be considered a priority.

Ocular vessel patterning in zebrafish is indirectly regulated by Hedgehog signaling.

The superficial ocular vasculature of the embryonic zebrafish develops in a highly stereotypic manner and hence provides a convenient model for studying molecular mechanisms that regulate vascular patterning. We have used transgenic zebrafish embryos in which all endothelial cells express enhanced Green Fluorescent Protein and small molecule inhibitors to examine the contribution of two signaling pathways, vascular endothelial growth factor (VEGF) and Hedgehog (Hh) pathways, to the development of the superficial system. We find that most, but not all vessels of the superficial system depend on VEGF signaling for their growth. Hh signaling appears to limit superficial vessel growth over the dorsal eye and is required to promote superficial vessel growth over the ventral eye. These effects of Hh signaling are indirect. Our initial analyses of factors that regulate growth and patterning of superficial ocular vessels suggest that early patterning events in the embryo during organogenesis stages could influence vascular patterning later on. By studying development of specific vascular systems it should be possible to identify new roles for signaling pathways in regulating vascular development.

A multi species evaluation of the radiation dosimetry of [11C]erlotinib, the radiolabeled analog of a clinically utilized tyrosine kinase inhibitor.

INTRODUCTION: Erlotinib is a tyrosine kinase inhibitor prescribed for non-small cell lung cancer (NSCLC) patients bearing epidermal growth factor receptor mutations in the kinase domain. The objectives of this study were to (1) establish a human dosimetry profile of [11C]erlotinib and (2) assess the consistency of calculated equivalent dose across species using the same dosimetry model. METHODS: Subjects examined in this multi-species study included: a stage IIIa NSCLC patient, 3 rhesus macaque monkeys, a landrace pig, and 4 athymic nude-Fox1nu mice. [11C]erlotinib PET data of the whole body were acquired dynamically for up to 120min. Regions of interest (ROIs) were manually drawn to extract PET time activity curves (TACs) from identifiable organs. TACs were used to calculate time-integrated activity coefficients (residence times) in each ROI, which were then used to calculate the equivalent dose in OLINDA. Subject data were used to predict the equivalent dose to the organs of a 73.7kg human male. RESULTS: In three of four species, the liver was identified as the organ receiving the highest equivalent dose (critical organ). The mean equivalent doses per unit of injected activity to the liver based on human, monkey, and mouse data were 29.4µSv/MBq, 17.4±6.0µSv/MBq, and 5.27±0.25µSv/MBq, respectively. The critical organ based on the pig data was the gallbladder wall (20.4µSv/MBq) but the liver received a nearly identical equivalent dose (19.5µSv/MBq). CONCLUSIONS: (1) When designing PET studies using [11C]erlotinib, the liver should be considered the critical organ. (2) In organs receiving the greatest equivalent dose, mouse data underestimated the dose in comparison to larger species. However, the effective dose of [11C]erlotinib to the whole body of a 73.7kg man was predicted with good consistency based on mice (3.14±0.05µSv/MBq) or the larger species (3.46±0.25µSv/MBq).

Negative association of pretreatment cigarette use with smoking-induced striatal dopamine release in smokers receiving bupropion treatment.

BACKGROUND AND OBJECTIVES: In an effort to help identify factors that maintain heavy smoking, this study tested the association of pretreatment cigarette use (cigarettes per day) with striatal dopamine release during smoking-cessation treatment. METHODS: Thirteen regular smokers (≥10 cigarettes per day) were evaluated on parameters of smoking behavior, and they entered a smoking cessation treatment protocol, including bupropion administration and individual counseling for 2 months. On week 7 of treatment, 10 of the participants underwent brain scans using [(11) C]raclopride with positron emission tomography to assess smoking-induced dopamine release in the caudate nucleus and putamen, inferred from changes in dopamine D2 -type receptor availability. RESULTS: Receptor availability, measured as binding potential referred to non-displaceable uptake (BPND ) in both striatal regions re-demonstrated a significant decrease after smoking a cigarette; and pre-treatment cigarette use significantly negatively correlated with smoking-induced dopamine release in the caudate. CONCLUSIONS AND SIGNIFICANCE: The negative association of cigarette use with dopamine release suggests tolerance or down-regulation of the dopamine system by chronic smoking, or a pre-existing condition that promotes more frequent smoking. This association should be regarded as preliminary evidence that warrants verification. (Am J Addict 2016;25:486-492).

Differentiating Between Cancer and Inflammation: A Metabolic-Based Method for Functional Computed Tomography Imaging.

One of the main limitations of the highly used cancer imaging technique, PET-CT, is its inability to distinguish between cancerous lesions and post treatment inflammatory conditions. The reason for this lack of specificity is that [(18)F]FDG-PET is based on increased glucose metabolic activity, which characterizes both cancerous tissues and inflammatory cells. To overcome this limitation, we developed a nanoparticle-based approach, utilizing glucose-functionalized gold nanoparticles (GF-GNPs) as a metabolically targeted CT contrast agent. Our approach demonstrates specific tumor targeting and has successfully distinguished between cancer and inflammatory processes in a combined tumor-inflammation mouse model, due to dissimilarities in angiogenesis occurring under different pathologic conditions. This study provides a set of capabilities in cancer detection, staging and follow-up, and can be applicable to a wide range of cancers that exhibit high metabolic activity.

Identifying erlotinib-sensitive non-small cell lung carcinoma tumors in mice using [(11)C]erlotinib PET.

BACKGROUND: Non-small cell lung carcinoma (NSCLC) represents approximately 80% of lung cancer cases, and over 60% of these tumors express the epidermal growth factor receptor (EGFR). Activating mutations in the tyrosine kinase (TK) domain of the EGFR are detected in 10% to 30% of NSCLC patients, and evidence of their presence is a prerequisite for initiation of first-line therapy with selective TK inhibitors (TKIs), such as gefitinib and erlotinib. To date, the selection of candidate patients for first-line treatment with EGFR TKIs requires an invasive tumor biopsy to affirm the mutational status of the receptor. This study was designed to evaluate whether positron emission tomography (PET) of NSCLC tumor-bearing mice using [(11)C]erlotinib could distinguish erlotinib-sensitive from erlotinib-insensitive or erlotinib-resistant tumors. METHODS: Four human NSCLC cell lines were employed, expressing either of the following forms of the EGFR: (i) the wild-type receptor (QG56 cells), (ii) a mutant with an exon 19 in-frame deletion (HCC827 cells), (iii) a mutant with the exon 21 L858R point mutation (NCI-H3255 cells), and (iv) a double mutant harboring the L858R and T790M mutations (NCI-H1975 cells). Sensitivity of each cell line to the anti-proliferative effect of erlotinib was determined in vitro. In vivo PET imaging studies following i.v. injection of [(11)C]erlotinib were carried out in nude mice bearing subcutaneous (s.c.) xenografts of the four cell lines. RESULTS: Cells harboring activating mutations in the EGFR TK domain (HCC827 and NCI-H3255) were approximately 1,000- and 100-fold more sensitive to erlotinib treatment in vitro, respectively, compared to the other two cell lines. [(11)C]Erlotinib PET scans could differentiate erlotinib-sensitive tumors from insensitive (QG56) or resistant (NCI-H1975) tumors already at 12 min after injection. Nonetheless, the uptake in HCC827 tumors was significantly higher than that in NCI-H3255, possibly reflecting differences in ATP and erlotinib affinities between the EGFR mutants. CONCLUSIONS: [(11)C]Erlotinib imaging in mice differentiates erlotinib-sensitive NSCLC tumors from erlotinib-insensitive or erlotinib-resistant ones.

PET molecular imaging of angiogenesis with a multiple tyrosine kinase receptor-targeted agent in a rat model of myocardial infarction.

PURPOSE: Angiogenesis plays a major role in tissue remodeling and repair after myocardial infarction (MI), and imaging it could provide information on the healing process. During angiogenesis, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and Tie receptors are upregulated, and this study aimed to develop a C-11 positron emission tomography (PET) agent for imaging angiogenesis by targeting these receptors. PROCEDURES: A VEGFR-2/Tie-2/PDGFRα inhibitor (N-(6-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-ureido]-phenoxy}-1H-benzoimidazol-2-yl)-2-(4-methyl-piperazin-1-yl)-acetamide (ATV-1)) was synthesized and labeled with C-11. MicroPET imaging of a rat MI model was compared to proteins expression by immunohistochemistry. RESULTS: [(11)C]ATV-1 specifically accumulated in the infracted region of the left ventricular (LV) lateral wall more than in the interventricular septal wall, but not in sham-operated or healthy animals. Moreover, [(11)C]ATV-1 uptake in the LV significantly correlated with Tie-2, VEGFR-2, and PDGFRα expression. CONCLUSION: Imaging angiogenesis in MI rats using [(11)C]ATV-1 and PET has been demonstrated. These results merit further research and development of more hydrophilic modified [(11)C]ATV-1 as a PET tracer.

Localization of parathyroid adenoma by ¹¹C-choline PET/CT: preliminary results.

PURPOSE: This prospective pilot study was aimed to evaluate ¹¹C-choline PET/CT (choline) as a tool for localization of parathyroid adenoma (PTA). METHODS: Forty patients with biochemical hyperparathyroidism underwent choline and 99mTc-MIBI imaging within a median interval of 56 days. Choline and MIBI images were analyzed and correlated with each other, with additional modalities such as ultrasound, CT, MRI, and with surgical findings, when available. RESULTS: Thirty-seven of forty cases were choline-positive, and 3 were choline-negative. Choline uptake on PET was identified with corresponding nodules on CT of the PET/CT, yielding precise localization. Twenty of thirty-seven foci were located in typical sites in the neck, and 17 were ectopic. Clear visualization of PTA was achieved in 33 of 37, whereas findings in 4 cases were suspicious for PTA. MIBI was positive in 33 of 40 cases (22 clearly positive, 11 suspicious). In 29 of 40 cases, choline and MIBI were concordant, but choline findings were clearer in 9 of these 29 studies.At the time of writing, 27 patients had undergone surgery. In 24 cases, there was complete matching of choline with surgical findings of PTA. Overall in 23 cases, both choline and MIBI matched surgical findings of PTA. In 1 case, PTA was correctly localized on choline but not on MIBI, and in 2 cases, neither choline nor MIBI corresponded to the surgical findings. CONCLUSIONS: These preliminary results indicate that the combined functional and anatomical modality of choline PET/CT is a promising tool for PTA localization, providing clearer images than MIBI, equal or better accuracy, and quicker and easier acquisition.

Rat imaging and in vivo stability studies using [11C]-dimethyl-diphenyl ammonium, a candidate agent for PET-myocardial perfusion imaging.

BACKGROUND: PET myocardial perfusion imaging (MPI) holds several advantages over SPECT for diagnosing coronary artery disease. The short half-lives of prevailing PET-MPI agents hamper wider clinical application of PET in nuclear cardiology; prompting the development of novel PET-MPI agents. We have previously reported on the potential of radiolabeled ammonium salts, and particularly on that of [(11)C]dimethyl-diphenyl-ammonium ([(11)C]DMDPA), for cardiac PET imaging. This study was designed to improve the radiosynthesis and increase the yield of [(11)C]DMDPA, characterize more meticulously the kinetics of radioactivity distribution after its injection via micro-PET/CT studies, and further explore its potential for PET-MPI. METHODS: The radiosynthetic procedure of [(11)C]DMDPA was improved with respect to the previously reported one. The kinetics of radioactivity distribution following injection of [(11)C]DMDPA were investigated in juvenile and young adult male SD rats using microPET/CT, and compared to those of [(13)N]NH3. Furthermore, the metabolic fate of [(11)C]DMDPA in vivo was examined after its injection into rats. RESULTS: Following a radiosynthesis time of 25-27 min, 11.9 ± 1.1 GBq of [(11)C]DMDPA was obtained, with a 43.7% ± 4.3% radiochemical yield (n = 7). Time activity curves calculated after administration of [(11)C]DMDPA indicated rapid, high and sustained radioactivity uptake in hearts of both juvenile and young adult rats, having a two-fold higher cardiac radioactivity uptake compared to [(13)N]NH3. Accordingly, at all time points after injection to both juvenile and young adult rats, image quality of the left ventricle was higher with [(11)C]DMDPA compared to [(13)N]NH3. In vivo stability studies of [(11)C]DMDPA indicate that no radioactive metabolites could be detected in plasma, liver and urine samples of rats up to 20 min after injection, suggesting that [(11)C]DMDPA is metabolically stable in vivo. CONCLUSIONS: This study further illustrates that [(11)C]DMDPA holds, at least in part, essential qualities required from a PET-MPI probe. Owing to the improved radiosynthetic procedure reported herein, [(11)C]DMDPA can be produced in sufficient amounts for clinical use.

Amyloid-ß positron emission tomography imaging probes: a critical review.

The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-ß deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-ß plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients.