Advances in PET myocardial perfusion imaging: F-18 labeled tracers

Coronary artery disease and its related cardiac disorders represent the most common cause of death in the USA and Western world. Despite advancements in treatment and accompanying improvements in outcome with current diagnostic and therapeutic modalities, it is the correct assignment of these diagnostic techniques and treatment options which are crucial. From a diagnostic standpoint, SPECT myocardial perfusion imaging (MPI) using traditional radiotracers like thallium-201 chloride, Tc-99m sestamibi or Tc-99m tetrofosmin is the most utilized imaging technique. However, PET MPI using N-13 ammonia, rubidium-82 chloride or O-15 water is increasing in availability and usage as a result of the growing number of medical centers with new-generation PET/CT systems taking advantage of the superior imaging properties of PET over SPECT. The routine clinical use of PET MPI is still limited, in part because of the short half-life of conventional PET MPI tracers. The disadvantages of these conventional PET tracers include expensive onsite production and inconvenient on-scanner tracer administration making them unsuitable for physical exercise stress imaging. Recently, two F-18 labeled radiotracers with longer radioactive half-lives than conventional PET imaging agents have been introduced. These are flurpiridaz F 18 (formerly known as F-18 BMS747158-02) and F-18 fluorobenzyltriphenylphosphonium. These longer half-life F-18 labeled perfusion tracers can overcome the production and protocol limitations of currently used radiotracers for PET MPI.     

<Superscript>18</Superscript>F-labelled annexin V: a PET tracer for apoptosis imaging

Annexin V can be used to detect apoptotic cells in vitro and in vivo, based on its ability to identify extracellular phosphatidylserine, which arises during apoptosis. In the present study, we examined the synthesis of fluorine-18 labelled annexin V as a positron emission tomography tracer for apoptosis imaging. The distribution of [¹⁸F]annexin V and technetium-99m labelled annexin V, a well-characterised SPET tracer for apoptosis imaging, was compared. [¹⁸F]annexin V was synthesised using N-succinimidyl 4-[¹⁸F]fluorobenzoate as an ¹⁸F labelling reagent. Synthesised and purified [¹⁸F]annexin V was confirmed by SDS-PAGE. In an ex vivo imaging experiment, [¹⁸F]annexin V was intravenously injected into rats 24 h after the induction of myocardial ischaemia, and accumulation in the left ventricle was examined. [¹⁸F]annexin V accumulated in the infarct area of the left ventricle, where apoptotic cells were observed. In separate experiments, [¹⁸F]annexin V or [^99mTc]annexin V was intravenously injected into ischaemic or normal animals, and the distribution of the tracers was compared. In ischaemic animals, accumulation of [¹⁸F]annexin V and [^99mTc]annexin V in the infarct area was about threefold higher than in the non-infarct area. Furthermore, the ratio of accumulation in the normal heart to the blood radioactivity was not significantly different between the tracers. In normal animals, however, the uptake of [¹⁸F]annexin V in the liver, spleen and kidney was much lower than that of [^99mTc]annexin V. The low uptake of [¹⁸F]annexin V in these organs might represent an advantage over [^99mTc]annexin V.     

18F-labelled N,N-dimethylamphetamine analogues for brain imaging studies

The radiochemical yields of nine N,N-dimethyl-2-(substituted phenyl)-isopropylamines (amphetamine analogues) were determined following reaction with [¹⁸F]acetyl hypofluorite in a 0.1 M HCl solution at room temperature. The meta-dimethoxy substituted amphetamines gave the highest radiofluorination yields (24–32%, at EOB). Purification of the ¹⁸F-labelled amphetamines was achieved in 10–20 min. 5-¹⁸F-2,4-Dimethoxy-N,N-dimethylamphetamine (5-¹⁸F-2,4-DNNA) was utilized to determine brain and lung uptake in rats. Positron emission tomography studies were conducted in a dog to determine the dynamic brain uptake and retention of this agent. The 5-¹⁸F-2,4-DNNA exhibited decreased initial uptake and more rapid loss of radioactivity in cerebral tissue compared to the iodinated homologue.     

Preclinical evaluation of BAY 1075553, a novel 18F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer

Purpose

Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer and is therefore being explored as a biomarker for diagnosing and staging of the disease. Here we report preclinical data on BAY 1075553 (a 9:1 mixture of (2S,4S)- and (2R,4S)-2-[¹⁸F]fluoro-4-phosphonomethyl-pentanedioic acid), a novel ¹⁸F-labelled small molecule inhibitor of PSMA enzymatic activity, which can be efficiently synthesized from a direct radiolabelling precursor.

Methods

The ¹⁸F-radiolabelled stereoisomers of 2-[¹⁸F]fluoro-4-(phosphonomethyl)-pentanedioic acid were synthesized from their respective isomerically pure precursors dimethyl 2-{[bis(benzyloxy)phosphoryl]methyl}-4-(tosyloxy)pentanedioate. In vivo positron emission tomography (PET) imaging and biodistribution studies were conducted in mice bearing LNCaP, 22Rv1 and PC-3 tumours. Pharmacokinetic parameters and dosimetry estimates were calculated based on biodistribution studies in rodents. For non-clinical safety assessment (safety pharmacology, toxicology) to support a single-dose human microdose study, off-target effects in vitro, effects on vital organ functions (cardiovascular in dogs, nervous system in rats), mutagenicity screens and an extended single-dose study in rats were conducted with the non-radioactive racemic analogue of BAY 1075553.

Results

BAY 1075553 showed high tumour accumulation specific to PSMA-positive tumour-bearing mice and was superior to other stereoisomers tested. Fast clearance of BAY 1075553 resulted overall in low background signals in other organs except for high uptake into kidney and bladder which was mainly caused by renal elimination of BAY 1075553. A modest uptake into bone was observed which decreased over time indicating organ-specific uptake as opposed to defluorination of BAY 1075553 in vivo. Biodistribution studies found highest organ doses for kidneys and the urinary bladder wall resulting in a projected effective dose (ED) in humans of 0.0219 mSv/MBq. Non-clinical safety studies did not show off-target activity, effects on vital organs function or dose-dependent adverse effects.

Conclusion

BAY 1075553 was identified as a promising PET tracer for PSMA-positive prostate tumours in preclinical studies. BAY 1075553 can be produced using a robust, direct radiosynthesis procedure. Pharmacokinetic, toxicology and safety pharmacology studies support the application of BAY 1075553 in a first-in-man microdose study with single i.v. administration.     

Detection of musculoskeletal infection with 18F-FDG PET: review of the current literature

There are several studies on (18)F-FDG PET in the evaluation of musculoskeletal infection; however, a search of the literature failed to identify any large-scale studies. The 7 articles reviewed included 273 cases of suspected musculoskeletal infection evaluated by (18)F-FDG PET. This method was found to be sensitive and specific in the evaluation of chronic and acute osteomyelitis and prosthetic infection. Furthermore, (18)F-FDG PET was accurate in the evaluation of infection at previous surgical sites even within 12 mo of surgery. The current literature suggests that (18)F-FDG PET is a highly accurate method to detect musculoskeletal infection.     

18F-FDG和18F-FLT PET/CT在肺部良恶性肿瘤鉴别诊断中的价值

目的:分析18F-FDG(18F-脱氧葡萄糖)和18F-FLT(18F-胸腺嘧啶)两种显像剂的PET/CT检查在肺部肿瘤中的不同影像学表现,提高PET/CT在肺部良恶性肿瘤鉴别诊断中价值,从而为临床治疗方案的选择提供可靠依据。方法:收集肺肿瘤患者55例为研究对象,其中男性33例,女性22例,年龄17～82岁,28例为肺内孤立肿块,其余为2～3个肿块,肿块大小0.6～11.0cm,所有患者均行肺部18 F-FDG和18 F-FLT PET/CT检查,分析18 F-FDG和18 F-FLT标准摄取值(SUV)与肺肿瘤患者的年龄、肿块大小及病理类型等相互关系和统计学意义。结果:18 F-FDG和18 F-FLT PET/CT的SUV与肺肿瘤患者的年龄、肿块大小均无统计学差异(P>0.05),18 F-FDG PET/CT的SUV与患者的病理类型亦无统计学差异(P>0.05),而18F-FLT PET/CT的SUV与患者的病理类型有统计学差异(P<0.05)。结论:肺肿瘤患者的肿块病理类型是影响18F-FLT PET/CT的SUV的重要因素,18F-FLT PET/CT的SUV在肺部良恶性肿瘤鉴别诊断中具有重要的价值。     

A new 18F-labelled derivative of the MMP inhibitor CGS 27023A for PET: Radiosynthesis and initial small-animal PET studies

The CGS 27023A derivative (R)-2-(N-((6-fluoropyridin-3-yl)methyl)-4-methoxyphenyl-sulphonamido)-N-hydroxy-3-methylbutanamide 1a was identified as a very potent matrix metalloproteinase inhibitor. Here, we describe a one-step radiosynthesis of the target compound [¹⁸F]1a. The syntheses of [¹⁸F]1a resulted in a radiochemical yield of 12.1±5.9% (decay-corrected), a radiochemical purity of 98.8±0.6%, and a specific activity of 39±27 GBq/μmol at the end of synthesis within 160±18 min from the end of radionuclide production (n=5). Initial small-animal PET studies in wild-type mice (C57/BL6) showed no unfavourable tissue accumulation of [¹⁸F]1a.     

PET imaging of musculoskeletal tumours with fluorine-18 alpha-methyltyrosine: comparison with fluorine-18 fluorodeoxyglucose PET

Fluorine-18 labelled alpha-methyltyrosine (FMT) was developed for positron emission tomography (PET) imaging, and its potential for clinical application in patients with brain tumours has been demonstrated. This is the first trial to compare FMT with 18F-fluoro-2-deoxy-D-glucose (FDG) for the evaluation of musculoskeletal tumours. Seventy-five patients were examined with both FMT- and FDG-PET within a 2-week period. Imaging findings were visually inspected in conjunction with computed tomography and/or magnetic resonance imaging, and standardized uptake values (SUVs) for both FMT and FDG in lesions were also generated and compared with histological findings. A significant correlation between FMT and FDG SUVs was found for all lesions (r=0.769, P<0.0001), and mean values for malignant tumours were significantly higher than those for benign lesions in both FMT- and FDG-PET. The diagnostic sensitivities and specificities for malignancy were 72.7% and 84.9%, respectively, using FMT with a cut-off SUV of 1.2, and 72.7% and 66.0%, respectively, using FDG with a cut-off SUV of 1.9. The resultant accuracy with FMT was 81.3%, higher than that for FDG (68.0%), and the difference with respect to specificity was significant (chi2cal=5.0625, P<0.05). On the other hand, while a significant correlation was found between malignant tumour grade and SUV with both FMT- (rho=0.656) and FDG-PET (rho=0.815), only the latter demonstrated significant differences among grades I, II and III. FMT and FDG for PET appear equally effective at detecting musculoskeletal tumours. In evaluating musculoskeletal tumours, FMT may be superior to FDG in the differentiation between benign and malignant tumours, while FDG may be the better choice for non-invasive malignancy grading.     

非骨化性纤维瘤18F-FDG PET/CT显像1例及文献回顾

笔者报道了1例发生在中年女性右侧胫骨近端的非骨化性纤维瘤（NOF）的X线、磁共振成像及PET/CT影像表现,并通过文献回顾总结了NOF的18F-氟脱氧葡萄糖（FDG） PET/CT影像表现。关于NOF的18F-FDG PET/CT检查的报道不多,充分认识其影像征象,有助于获取更多的信息,进而做出准确诊断。     

Imaging of the brain serotonin transporters (SERT) with 18F-labelled fluoromethyl-McN5652 and PET in humans

Purpose

[¹¹C]DASB is currently the most frequently used highly selective radiotracer for visualization and quantification of central SERT. Its use, however, is hampered by the short half-life of ¹¹C, the moderate cortical test–retest reliability, and the lack of quantifying endogenous serotonin. Labelling with ¹⁸F allows in principle longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly use the new highly SERT-selective ¹⁸F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[¹⁸F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification.

Methods

The PET data from five healthy volunteers (three men, two women, age 39?±?10?years) coregistered with individual MRI scans were semiquantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and total distribution volumes (V _T) were calculated using a two-tissue compartment model and arterial input function measurements were corrected for metabolite/plasma data. Standardized uptake region-to-cerebellum ratios as a measure of specific radiotracer accumulation were compared with those of a [¹¹C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38?±?8?years).

Results

The two-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume (V _T) demonstrated good identifiability based on the coefficients of variation (COV) for the volumes of interest in SERT-rich and cortical areas (COV V _T <10%). Compared with [¹¹C]DASB PET, there was a tendency to lower mean uptake values in (+)-[¹⁸F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[¹⁸F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans.

Conclusion

The results showed that (+)-[¹⁸F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of the long half-life of ¹⁸F, the widespread use within a satellite concept seems feasible.     

Brain tumour imaging with PET: a comparison between [18F]fluorodopa and [11C]methionine

Imaging of amino acid transport in brain tumours is more sensitive than fluorine-18 2-fluoro-deoxyglucose positron emission tomography (PET). The most frequently used tracer in this field is carbon-11 methionine (MET), which is unavailable for PET centres without a cyclotron because of its short half-life. The purpose of this study was to evaluate the performance of 3,4-dihydroxy-6-[¹⁸F]fluoro-phenylalanine (FDOPA) in this setting, in comparison with MET. Twenty patients with known supratentorial brain lesions were referred for PET scans with FDOPA and MET. The diagnoses were 18 primary brain tumours, one metastasis and one non-neoplastic cerebral lesion. All 20 patients underwent PET with FDOPA (100 MBq, 20 min p.i.), and 19 of them also had PET scans with MET (800 MBq, 20 min p.i.). In all but one patient a histological diagnosis was available. In 15 subjects, histology was known from previous surgical interventions; in five of these patients, as well as in four previously untreated patients, histology was obtained after PET. In one untreated patient, confirmation of PET was possible solely by correlation with MRI; a histological diagnosis became available 10 months later. MET and FDOPA images matched in all patients and showed all lesions as hot spots with higher uptake than in the contralateral brain. Standardised uptake value ratios, tumour/contralateral side (mean±SD), were 2.05±0.91 for MET and 2.04±0.53 for FDOPA (NS). The benign lesion, which biopsy revealed to be a focal demyelination, was false positive, showing increased uptake of MET and FDOPA. We conclude that FDOPA is accurate as a surrogate for MET in imaging amino acid transport in malignant cerebral lesions for the purpose of visualisation of vital tumour tissue. It combines the good physical properties of ¹⁸F with the pharmacological properties of MET and might therefore be a valuable PET radiopharmaceutical in brain tumour imaging.     

Synthesis and evaluation of a 18F-labelled recombinant annexin-V derivative, for identification and quantification of apoptotic cells with PET.

In this report, we describe the synthesis of 4-[18F]-fluorobenzoyl-annexin V (4-[18F]FBA). In a four-step procedure, 4-[18F]FBA was synthesised with a microcomputer controlled, automated module within 90min. The radiochemical yield was in the range of 15-20% (corrected for decay) with a specific activity of more than 35GBq/micromol. The specific binding was confirmed by studies of 4-[18F]FBA with phosphatidylserine-containing liposomes. The biological activity of 4-[18F]FBA was verified by measuring its binding to Jurkat T-cell lymphoblasts after induction of apoptosis as compared to control cells without apoptosis. 4-[18F]FBA seems to be a suited tracer to measure apoptotic activity in vivo.     

Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature

Imaging that can detect pathophysiologic change in the brain holds great promise for diagnostic assessment of patients with Alzheimer disease (AD) and dementia. Although a previous metaanalysis centering on literature from 1990 to 2000 showed a summary accuracy of 86% for (18)F-FDG PET for AD diagnosis, the clinical value was considered uncertain because of methodologic shortcomings. Review of the recent literature since 2000 demonstrates that the evidence for (18)F-FDG PET in assessment of dementia has increased with new studies that include autopsy confirmation, wide-diagnostic-spectrum recruitment in primary care settings, historical and prospective cohort studies, and multicenter data analyses. These data support the role of (18)F-FDG PET as an effective and useful adjunct to other diagnostic information in the assessment of patients with symptoms of dementia. Findings are in line with recently revised diagnostic criteria of AD that for the first time recognize the unique role of biomarker evidence in disease definition.     

Production of 18F-labelled 2-deoxy-2-fluoro-D-glocose and preliminary imaging results

To allow an additional approach to the study of brain metabolism in our laboratory, the synthesis of ¹⁸F-2-deoxy-2-fluoro-D-glucose (¹⁸FDG) has been adapted by the development of simple, reliable control techniques for routine use. By positron emission computed tomography, it has been established, in the baboon Papio papio, that there was a correlation between an epileptic focus and an increase in glucose incorporation. On the other hand, in man, a comparison between the local glucose utilization, cerebral blood flow and oxygen consumption has showed, in patients with ischaemic strokes, a disruption in the normal flow-metabolism couple.