[<Superscript>18</Superscript>F]FLT PET for diagnosis and staging of thoracic tumours

The nucleoside analogue 3'-deoxy-3'-[¹⁸F]fluorothymidine (FLT) has been introduced for imaging of tumour cell proliferation by positron emission tomography (PET). This study evaluated the use of FLT in patients with thoracic tumours prior to treatment. Whole-body FLT PET was performed in 16 patients with 18 tumours [17 thoracic tumours (nine non-small cell lung cancers, five oesophageal carcinomas, two sarcomas, one Hodgkin's lymphoma) and one renal carcinoma] before treatment. Fluorine-18 fluorodeoxyglucose (FDG) PET was performed for comparison except in those patients with oesophageal carcinoma. For semi-quantitative analysis, the average and maximum standardised uptake values (avgSUV and maxSUV, respectively) (FLT, 114±20 min p.i.; FDG, 87±8 min p.i.; 50% isocontour region of interest) was calculated. All 17 thoracic tumours and 19/20 metastases revealed significant FLT accumulation, resulting in easy delineation from surrounding tissue. The additional small grade 1 renal carcinoma was not detected with either FLT or FDG. In most lung tumours (avgSUV 1.5–8.2) and metastases, FLT showed intense uptake. However, one of two spinal bone metastases was missed owing to the high physiological FLT uptake in the surrounding bone marrow. Oesophageal carcinoma primaries (avgSUV 2.7–10.0) and occasional metastases showed particularly favourable tumour/non-tumour contrast. Compared with FDG, tumour uptake of FLT was lower (avgSUV, P=0.0006; maxSUV, P=0.0001), with a significant linear correlation (avgSUV, r²=0.45; maxSUV, r²=0.49) between FLT and FDG. It is concluded that FLT PET accurately visualises thoracic tumour lesions. In the liver and the bone marrow, high physiological FLT uptake hampers detection of metastases. On the other hand, FLT may be favourable for imaging of brain metastases owing to the low physiological uptake.     

<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.     

Parametric renal blood flow imaging using [<Superscript>15</Superscript>O]H<Subscript>2</Subscript>O and PET

Purpose  The quantitative assessment of renal blood flow (RBF) may help to understand the physiological basis of kidney function and allow an evaluation of pathophysiological events leading to vascular damage, such as renal arterial stenosis and chronic allograft nephropathy. The RBF may be quantified using PET with H₂ ¹⁵O, although RBF studies that have been performed without theoretical evaluation have assumed the partition coefficient of water (p, ml/g) to be uniform over the whole region of renal tissue, and/or radioactivity from the vascular space (V _A. ml/ml) to be negligible. The aim of this study was to develop a method for calculating parametric images of RBF (K ₁, k ₂) as well as V _A without fixing the partition coefficient by the basis function method (BFM). Methods  The feasibility was tested in healthy subjects. A simulation study was performed to evaluate error sensitivities for possible error sources. Results  The experimental study showed that the quantitative accuracy of the present method was consistent with nonlinear least-squares fitting, i.e. K _1,BFM=0.93K _1,NLF−0.11 ml/min/g (r=0.80, p<0.001), k _2,BFM=0.96k _2,NLF−0.13 ml/min/g (r=0.77, p<0.001), and V _A,BFM=0.92V _A,NLF−0.00 ml/ml (r=0.97, p<0.001). Values of the Akaike information criterion from this fitting were the smallest for all subjects except two. The quality of parametric images obtained was acceptable. Conclusion  The simulation study suggested that delay and dispersion time constants should be estimated within an accuracy of 2 s. V _A and p cannot be neglected or fixed, and reliable measurement of even relative RBF values requires that V _A is fitted. This study showed the feasibility of measurement of RBF using PET with H₂ ¹⁵O.     

Synthesis and evaluation of [11C]FR194921 as a nonxanthine-type PET tracer for adenosine A1 receptors in the brain

This report describes the synthesis of [¹¹C]2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone ([¹¹C]FR194921), a highly selective, nonxanthine-type adenosine A₁ receptor antagonist, used in brain imaging in rats and conscious monkeys as a potential novel PET tracer. [¹¹C]FR194921 was successfully synthesized in 19 min after [¹¹C]CH₃I formation. The radiochemical yield was 38±3%; and radioactivity was 4.1±0.4 GBq, calculated from end of synthesis; radiochemical purity was higher than 99%; and the specific radioactivity was 25.0±8.1 GBq μmol⁻¹ (n=5). In a rat experiment, the distribution of [¹¹C]FR194921 was higher in the hippocampus, striatum and cerebellum regions. This accumulation was significantly decreased by approximately 50% by pretreatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A₁ receptor antagonist, which indicated specific binding of the radioligand to adenosine A₁ receptors. In conscious monkey PET experiments, [¹¹C]FR194921 accumulated in several regions of the brain, especially in the occipital cortex, thalamus and striatum. These results suggest that [¹¹C]FR194921 can be used as an agent for imaging adenosine A₁ receptors in vivo by positron emission tomography (PET).     

Neurofunctional imaging of the pancreas utilizing the cholinergic PET radioligand [<Superscript>18</Superscript>F]4-fluorobenzyltrozamicol

The pancreas is one of the most heavily innervated peripheral organs in the body. Parasympathetic and sympathetic neurons terminate in the pancreas and provide tight control of endocrine and exocrine functions. The aim of this study was to determine whether the pancreas can be imaged with a radioligand that binds to specific neuroreceptors. Using fluorine-18 4-fluorobenzyltrozamicol (FBT), which binds to the presynaptic vesicular acetylcholine transporter, positron emission tomography scans were performed in four adult mice, two adult rhesus monkeys, and one adult human. In these mammals, the pancreas is intensely FBT avid, with uptake greater than in any other organ at 30, 60, and 90 min. The maximum standardized uptake value (SUV) ratios of pancreas to liver, for example, ranged from 1.4 to 1.7 in rhesus monkeys (mean 1.6; median 1.7) and from 1.9 to 4.7 (mean 3.24; median 3.02) in mice. The maximum SUV ratio of pancreas to liver in the human was 1.8. These data suggest that neuroreceptor imaging of the pancreas in vivo is feasible in animal models and humans. This imaging could allow researchers to interrogate functions under control of the autonomic nervous system in the pancreas, with applications possible in transplanted and native pancreata. Also, as beta cell function is intimately related to parasympathetic cholinergic input, FBT activity in the pancreas may correlate with insulin-producing beta cell mass. This could ultimately provide a method of in vivo imaging in animal models and humans for diabetes research.     

Synthesis and in vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand

The potential of a ¹¹C-labeled selective sigma₁ receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([¹¹C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma₁ receptors in the central nervous system and peripheral organs. [¹¹C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [¹¹C]CH₃I, with the decay-corrected radiochemical yield of 39 ± 5% based on [¹¹C]CH₃I and with the specific activity of 53 ± 17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [¹¹C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [¹¹C]SA6298 by these organs except for the small intestine, but significant displacement of [¹¹C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (−)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma₁ receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [¹¹C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [¹¹C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma₁ receptors. The saturable brain uptake of [¹¹C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a relatively high uptake was found in the cortex, thalamus, striatum, and cerebellum. These results have indicated a receptor-mediated uptake of the tracer to some extent in the brain and peripheral organs. However, the tracer has a limited potential for the PET study of the brain receptors because of a relatively high nonspecific binding.     

Positron emission tomography with [<Superscript>18</Superscript>F]FDOPA and [<Superscript>18</Superscript>F]FDG in the imaging of small cell lung carcinoma: preliminary results

Small cell lung carcinomas (SCLC) express neuroendocrine markers, and dihydroxyphenylalanine (DOPA) is known to accumulate in neuroendocrine tumours. This study was performed with the aim of evaluating the uptake of 3,4-dihydroxy-6-¹⁸F-fluoro-phenylalanine ([¹⁸F]FDOPA) by SCLC, based on comparison with the results of fluorine-18 fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) and standard imaging procedures. [¹⁸F]FDG PET and [¹⁸F]FDOPA PET were performed on four patients with newly diagnosed SCLC. There was agreement between the results of [¹⁸F]FDOPA PET and [¹⁸F]FDG PET in four tumoural sites out of 11, whereas [¹⁸F]FDG PET and standard imaging procedures were in full agreement. A semi-quantitative analysis based on standardised uptake values (SUVs) was performed in order to compare [¹⁸F]FDG and [¹⁸F]FDOPA tumour uptake. The median [¹⁸F]FDG SUV_max was 5.9 (with a 95% confidence interval from 4.4 to 9.2), while the median [¹⁸F]FDOPA SUV_max was 1.9 (with a 95% confidence interval from 1.6 to 3.8). The difference between [¹⁸F]FDG SUV_max and [¹⁸F]FDOPA SUV_max was significant (P<0.01). [¹⁸F]FDOPA PET appeared less sensitive than [¹⁸F]FDG PET and standard imaging procedures in the staging of SCLC. No clear relation between [¹⁸F]FDOPA uptake and positivity of neuroendocrine markers on immunohistochemistry emerged from these preliminary results; however, since [¹⁸F]FDOPA uptake may reflect better differentiation of the tumour, and possibly a better prognosis, this point warrants clarification in a larger study.     

[1-<Superscript>11</Superscript>C]Acetate uptake is not increased in renal cell carcinoma

Purpose The purpose of this study was to investigate the potential of [1-¹¹C]acetate (AC) as a metabolic tracer for renal cell cancer in human subjects. Methods Twenty-one patients with suspected kidney tumours were investigated with AC and dynamic PET. AC uptake was scored on a five-step scale. Tumour localisation was known from CT/MRI. Histology was available in 18/21 patients. The results in these 18 patients are reported. Results AC uptake by the tumour was less than (n = 11), equal to (n = 5) or higher than (n = 2) uptake in the surrounding renal parenchyma. Histological tumour types showed a typical distribution, with a predominance of clear cell carcinomas (n = 14) and only a small number of papillary cell carcinomas (n = 2) and oncocytomas (n = 2). Only the benign oncocytomas were highly positive with AC. Conclusion In most kidney tumours the AC accumulation was not higher than in normal kidney parenchyma. Therefore, AC PET cannot be recommend for the characterisation of a renal mass.     

Quantification of adenosine A<Subscript>2A</Subscript> receptors in the human brain using [<Superscript>11</Superscript>C]TMSX and positron emission tomography

Purpose [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX) is a positron-emitting adenosine A_2A receptor (A2AR) antagonist for visualisation of A2AR distribution by positron emission tomography (PET). The aims of this paper were to use a kinetic model to analyse the behaviour of [¹¹C]TMSX in the brain and to examine the applicability of the Logan plot. We also studied the applicability of a simplified Logan plot by omitting metabolite correction and arterial blood sampling. Methods The centrum semiovale was used as a reference region on the basis of a post-mortem study showing that it has a negligibly low density of A2ARs. Compartmental analysis was performed in five normal subjects. Parametric images of A2AR binding potential (BP) were also generated using a Logan plot with or without metabolite correction and with or without arterial blood sampling. To omit arterial blood sampling, we applied a method to extract the plasma-related information using independent component analysis (EPICA). Results The estimated K ₁/k ₂ was confirmed to be common in the centrum semiovale and main cortices. The three-compartment model was well fitted to the other regions using the fixed value of K ₁/k ₂ estimated from the centrum semiovale. The estimated BPs using the Logan plot matched those derived from compartment analysis. Without the metabolite correction, the estimate of BP underestimated the true value by 5%. The estimated BPs agreed regardless of arterial blood sampling. Conclusion A three-compartment model with a reference region, the centrum semiovale, describes the kinetic behaviour of [¹¹C]TMSX PET images. A2ARs in the human brain can be visualised as a BP image using [¹¹C]TMSX PET without arterial blood sampling.     

Adding <Superscript>11</Superscript>C-methionine PET to the EORTC prognostic factors in grade 2 gliomas

Purpose The management of adult patients with grade 2 gliomas remains a challenge for the clinical neuro-oncologist. Several clinical prognostic factors appear to be as important as treatment factors in determining outcome. From the European Organisation for Research and Treatment of Cancer (EORTC) trials 22844 and 22845, a prognostic scoring system has been proposed based on the presence of unfavourable prognostic factors. The aim of the present study was to assess the additional prognostic value of ¹¹C-methionine (MET) measured by positron emission tomography (PET) in the setting of the EORTC prognostic scoring system. Methods In this retrospective review, 129 patients with supratentorial grade 2 gliomas were subjected to a PET study as part of the pre-treatment tumour investigation. One hundred and three cases were classified as low-risk patients (0–2 unfavourable factors) and 26 cases as high-risk patients (3–5 unfavourable factors) according to the EORTC criteria. MET PET was evaluated as an extra prognostic factor in both groups. Results In the high-risk group, patients with high MET uptake had a worse outcome than patients with low MET uptake. A similar trend was found for the low-risk group in patients with oligodendrocytic tumours. Conclusions Our findings further strengthen the role of MET PET as an important prognostic tool in the management of this group of patients.     

Improved synthesis of [<Superscript>11</Superscript>C]SA4503, [<Superscript>11</Superscript>C]MPDX and [<Superscript>11</Superscript>C]TMSX by use of [<Superscript>11</Superscript>C]methyl triflate

Recently we have clinically used three new radioligands, [11C]SA4503, [11C]MPDX, and [11C]TMSX, for mapping sigma1, adenosine A1, and adenosine A2A receptors, respectively, in the human brain by positron emission tomography. These radioligands are synthesized by methylation of the respective demethyl precursor with [11C]methyl iodide. Here we demonstrate the improved syntheses of these compounds by use of [11C]methyl triflate, a highly reactive alternative to [11C]methyl iodide.     

High-quality <Superscript>124</Superscript>I-labelled monoclonal antibodies for use as PET scouting agents prior to <Superscript>131</Superscript>I-radioimmunotherapy

Purpose Monoclonal antibodies (MAbs) labelled with ¹²⁴I are an attractive option for quantitative imaging with positron emission tomography (PET) in a scouting procedure prior to ¹³¹I-radioimmunotherapy (¹³¹I-RIT). In this study, three important items in the labelling of MAbs with ¹²⁴I were introduced to obtain optimal and reproducible product quality: restoration of radiation-induced inorganic deterioration of the starting ¹²⁴I solution, radiation protection during and after ¹²⁴I labelling, and synchronisation of the I/MAb molar ratio.Methods A new method was applied, using an NaIO₃/NaI carrier mix, realising in one step >90% restoration of deteriorated ¹²⁴I into the iodide form and chemical control over the I/MAb molar ratio. Chimeric MAb (cMAb) U36 and the murine MAbs 425 and E48 were labelled with ¹²⁴I using the so-called Iodogen-coated MAb method, as this method provides optimal quality conjugates under challenging radiation conditions. As a standardising condition, NaIO₃/NaI carrier mix was added at a stoichiometric I/MAb molar ratio of 0.9. For comparison, MAbs were labelled with ¹³¹I and with a mixture of ¹²⁴I, ¹²³I, ¹²⁶I and ¹³⁰I.Results Labelling with ¹²⁴I in this setting resulted in overall yields of >70%, a radiochemical purity of >95%, and preservation of MAb integrity and immunoreactivity, including at the patient dose level (85 MBq). No significant quality differences were observed when compared with ¹³¹I products, while the iodine isotope mixture gave exactly the same labelling efficiency for each of the isotopes, excluding a different chemical reactivity of ¹²⁴I-iodide. The scouting performance of ¹²⁴I-cMAb U36 labelled at the patient dose level was evaluated in biodistribution studies upon co-injection with ¹³¹I-labelled cMAb U36, and by PET imaging in nude mice bearing the head and neck cancer xenograft line HNX-OE. ¹²⁴I-cMAb and ¹³¹I-cMAb U36 labelled with a synchronised I/MAb molar ratio gave fully concordant tissue uptake values. Selective tumour uptake was confirmed with immuno-PET, revealing visualisation of 15 out of 15 tumours.Conclusion These results pave the way for renewed evaluation of the potential of ¹²⁴I-immuno-PET for clinical applications.     

Quantification of human brain benzodiazepine receptors using [<Superscript>18</Superscript>F]fluoroethylflumazenil: a first report in volunteers and epileptic patients

Fluorine-18 fluoroethylflumazenil ([¹⁸F]FEF) is a tracer for central benzodiazepine (BZ) receptors which is proposed as an alternative to carbon-11 flumazenil for in vivo imaging using positron emission tomography (PET) in humans. In this study, [¹⁸F]FEF kinetic data were acquired using a 60-min two-injection protocol on three normal subjects and two patients suffering from mesiotemporal epilepsy as demonstrated by abnormal magnetic resonance imaging and [¹⁸F]fluorodeoxyglucose positron emission tomography. First, a tracer bolus injection was performed and [¹⁸F]FEF rapidly distributed in the brain according to the known BZ receptor distribution. Thirty minutes later a displacement injection of 0.01 mg/kg of unlabelled flumazenil was performed. Activity was rapidly displaced from all BZ receptor regions demonstrating the specific binding of [¹⁸F]FEF. No displacement was observed in the pons. Plasma input function was obtained from arterial blood sampling, and metabolite analysis was performed by high-performance liquid chromatography. Metabolite quantification revealed a fast decrease in tracer plasma concentration, such that at 5 min post injection about 70% of the total radioactivity in plasma corresponded to [¹⁸F]FEF, reaching 24% at 30 min post injection. The interactions between [¹⁸F]FEF and BZ receptors were described using linear compartmental models with plasma input and reference tissue approaches. Binding potential values were in agreement with the known distribution of BZ receptors in human brain. Finally, in two patients with mesiotemporal sclerosis, reduced uptake of [¹⁸F]FEF was clearly observed in the implicated left hippocampus.     

In vivo assessment of [<Superscript>11</Superscript>C]MRB as a prospective PET ligand for imaging the norepinephrine transporter

Purpose Antagonism of norepinephrine reuptake is now an important pharmacological strategy in the treatment of anxiety and depressive disorders, and many antidepressants have substantial potential occupancy of the norepinephrine transporter (NET) at recommended dosages. Despite the importance of understanding this transporter’s role in psychiatric disease and treatment, a suitable radioligand for studying NET has been slow to emerge. (S,S)-Methylreboxetine (MRB) is among the more promising ligands recently adapted for positron emission tomography (PET), and the present study aimed to evaluate its potential for use in higher primates. Methods Affinities for various brain targets were determined in vitro. PET studies were conducted in baboon under both test–retest and blocking conditions using 1 mg/kg nisoxetine. Results MRB has sixfold higher affinity for NET than the serotonin transporter, and negligible affinity for other sites. PET studies in baboons showed little regional heterogeneity in binding and were minimally affected by pretreatment with the NET antagonist nisoxetine. Conclusion Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [¹¹C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.     

Radiosynthesis and in vivo evaluation of N-[11C]methylated imidazopyridineacetamides as PET tracers for peripheral benzodiazepine receptors

Imidazopyridineacetoamide 5–8, a series of novel and potentially selective peripheral benzodiazepine receptor (PBR) ligands with affinities comparable to those of known PBR ligands, was investigated. Radiosyntheses of [¹¹C]5, 6, 7 or 8 was accomplished by N-methylation of the corresponding desmethyl precursors with [¹¹C]methyl iodide in the presence of NaH in dimethylformamide (DMF), resulting in 25% to 77% radiochemical yield and specific activitiy of 20 to 150 MBq/nmol. Each of the labeled compounds was injected in ddY mice, and the radioactivity and weight of dissected peripheral organs and brain regions were measured. Organ distribution of [¹¹C]7 was consistent with the known PBR distribution. Moreover, [¹¹C]7 showed the best combination of brain uptake and PBR binding, leading to its high retention in the olfactory bulb and cerebellum, areas where PBR density is high in mouse brain. Coinjection of PK11195 or unlabeled 7 significantly reduced the brain uptake of [¹¹C]7. These results suggest that [¹¹C]7 could be a useful radioligand for positron emission tomography imaging of PBRs.     

Synthesis and in vivo evaluation of [C]SA6298 as a PET sigma1 receptor ligand

The potential of a ¹¹C-labeled selective sigma₁ receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([¹¹C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma₁ receptors in the central nervous system and peripheral organs. [¹¹C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [¹¹C]CH₃I, with the decay-corrected radiochemical yield of 39 ± 5% based on [¹¹C]CH₃I and with the specific activity of 53 ± 17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [¹¹C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [¹¹C]SA6298 by these organs except for the small intestine, but significant displacement of [¹¹C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (−)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma₁ receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [¹¹C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [¹¹C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma₁ receptors. The saturable brain uptake of [¹¹C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a relatively high uptake was found in the cortex, thalamus, striatum, and cerebellum. These results have indicated a receptor-mediated uptake of the tracer to some extent in the brain and peripheral organs. However, the tracer has a limited potential for the PET study of the brain receptors because of a relatively high nonspecific binding.     

Adenosine A<Subscript>2A</Subscript> receptor imaging with [<Superscript>11</Superscript>C]KF18446 PET in the rat brain after quinolinic acid lesion: Comparison with the dopamine receptor imaging

We proposed [11C]KF18446 as a selective radioligand for mapping the adenosine A2A receptors being highly enriched in the striatum by positron emission tomography (PET). In the present study, we investigated whether [11C]KF18446 PET can detect the change in the striatal adenosine A2A receptors in the rat after unilateral injection of an excitotoxin quinolinic acid into the striatum, a Huntington's disease model, to demonstrate the usefulness of [11C]KF18446. The extent of the striatal lesion was identified based on MRI, to which the PET was co-registered. The binding potential of [11C]KF18446 significantly decreased in the quinolinic acid-lesioned striatum. The decrease was comparable to the decrease in the potential of [11C]raclopride binding to dopamine D2 receptors in the lesioned striatum, but seemed to be larger than the decrease in the potential of [11C]SCH 23390 binding to dopamine D1 receptors. Ex vivo and in vitro autoradiography validated the PET signals. We concluded that [11C]KF18446 PET can detect change in the adenosine A2A receptors in the rat model, and will provide a new diagnostic tool for characterizing post-synaptic striatopallidal neurons in the stratum.     

Preparation of the hypoxia imaging PET tracer [F]FAZA: reaction parameters and automation

¹⁸F-labeling of the nitroimidazole nucleoside analogue 1-(5-fluoro-5-deoxy--D-arabinofuranosyl)-2-nitroimidazole (FAZA) was developed to use this tracer in PET for detection of hypoxia. Parameters for labeling and hydrolysis were optimized with regard to amount of precursor, temperature and time. Labeling yields reached a maximum of 62±4% at 100 °C within 5 min using 5 mg of precursor. Hydrolysis was best performed with 1 mL of 0.1 N NaOH at 20 °C for 2 min. Transfer of these conditions to an automated synthesizer resulted in an overall radiochemical yield of 20.7±3.5%. Absolute yields at EOS were 9.8±2.3 GBq of [¹⁸F]FAZA ready for injection (n=21; 50 min after EOB; irradiation parameters: 35 μA, 60 min). Thus, a convenient approach suitable for large-scale production of [¹⁸F]FAZA was developed by an automated process.     

[<Superscript>18</Superscript>F]FLT-PET in oncology: current status and opportunities

In recent years, [¹⁸F]-fluoro-3-deoxy-3-L-fluorothymidine ([¹⁸F]FLT) has been developed as a proliferation tracer. Imaging and measurement of proliferation with PET could provide us with a non-invasive staging tool and a tool to monitor the response to anticancer treatment. In this review, the basis of [¹⁸F]FLT as a proliferation tracer is discussed. Furthermore, an overview of the current status of [¹⁸F]FLT-PET research is given. The results of this research show that although [¹⁸F]FLT is a tracer that visualises cellular proliferation, it also has certain limitations. In comparison with the most widely used PET tracer, [¹⁸F]FDG, [¹⁸F]FLT uptake is lower in most cases. Furthermore, [¹⁸F]FLT uptake does not always reflect the tumour cell proliferation rate, for example during or shortly after certain chemotherapy regimens. The opportunities provided by, and the limitations of, [¹⁸F]FLT as a proliferation tracer are addressed in this review, and directions are given for further research, taking into account the strong and weak points of the new tracer.