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H J Wester

Publications and source records attributed to H J Wester.

At least 19 recordsLinked to original sources
PubMed2007

Fluorine-18 labeling of peptides and proteins.

The pool of promising peptides worthy of investigation and evaluation for clinical use is continuously filled from different sources. Driven by the promising results obtained with peptides addressing somatostatin-2 receptor positive (sst2+) neuroendocrine tumours, other peptides targeting further receptor systems are being studied and evaluated. Progress in profiling the density and incidence of peptide hormone receptors in human cancer has initiated and will further promote research on the corresponding peptidic binders. In addition, industrial pharmaceutical research will be another significant source of peptides in the future. A recent prognosis revealed that about 50% of the drugs entering clinical trials in the next years will be peptides. The extensive research activities in genomics and proteomics will point out and quantify new and already known target structures upregulated in specific diseases. Based on the knowledge of their endogenous ligands or via selection of suitable candidates by phage display, suitable peptide ligands for e.g. membrane associated receptors can be identified and thus allow targeting of such binding sites. Thus, bioactive peptides specifically addressing relevant molecular targets are expected to become an important class of tracers, also due to the possibility of bridging imaging with therapeutic approaches. In this brief overview a summary of methods and strategies for the 18F-labeling of peptides and proteins is given.

Amination↗
PubMed2006

Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study.

Using PET with the opioidergic ligand [11C]diprenorphine, the authors demonstrate decreased tracer binding in the pineal gland of cluster headache patients vs healthy volunteers. Opioid receptor availability in the hypothalamus and cingulate cortex depended on the duration of the headache disorder. Therefore, the pathophysiology of cluster headache may relate to opioidergic dysfunction in circuitries generating the biologic clock.

Adult↗
PubMed2004

Targeting of gelatinase activity with a radiolabeled cyclic HWGF peptide.

Matrix metalloproteinases (MMPs) are a family of proteinases that play an important role in cancer as well as in numerous diseases. In this article, we describe the labeling of a phage display selected cyclic decapeptide containing the HWGF (histidine-tryptophane-glycine-phenylalanine) sequence to target MMP-2 and MMP-9. To evaluate the ability of this labeled peptide to monitor non invasively MMP-2 and MMP-9 activity, in vitro studies, biodistribution, competition studies and plasma metabolites analyses in Lewis Lung cancer tumor bearing mice were performed.

Animals↗
PubMed2003

Radiotracer-based strategies to image angiogenesis.

Tumour-induced angiogenesis plays an important role in tumour progression. Great efforts are made to develop therapeutic strategies to interfere with this process resulting in the starvation of the tumour. However, strategies to monitor conventional therapies seems to be inappropriate to control these approaches. Thus, there is a keen interest in developing methods supplying information about the corresponding therapeutical effects. Several radiotracer-based approaches focused on different targets in the angiogenic process are currently investigated. One class of tracers is based on matrix metalloproteinases inhibitors. These compounds show promising results in in vitro assays. However, initial data from in vivo studies using murine tumour models could not confirm successful non-invasive monitoring of MMP activity yet. Another strategy uses a radiolabelled single chain fragment against the ED-B domain of fibronectin, an extracellular matrix protein. Promising results demonstrated selective accumulation of the tracer in the tumour vasculature of a murine tumour model. Most of the studies are concentrated on the development of radiolabelled antagonists of the integrin alpha(v)beta(3). This heterodimeric transmembrane glycoprotein is involved in the migration of activated endothelial cells during formation of new vessels. Different compounds have been labelled with (18F), (111)In, (99m)Tc, (90)Y and several iodine isotopes. In in vitro assays most of them revealed high alpha(v)beta(3) affinity and selectivity. Moreover, in different murine tumour models successful non-invasive determination of alpha(v)beta(3) expression has been shown. Some of these approaches indicate that tumour-induced angiogenesis can be monitored in animal studies. Nevertheless, translation of these approaches into clinical settings allowing visualisation of tumour-induced angiogenesis in patients needs still to be demonstrated.

Animals↗
PubMed2002

PET imaging of somatostatin receptors: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide.

Because of the excellent nuclear properties of fluorine-18 and the growing interest in somatostatin receptor (sst) scintigraphy with PET, a novel carbohydrated (18)F-labelled sst ligand was developed and preclinically evaluated. Synthesis of N(alpha)-(1-deoxy- D-fructosyl)- N(epsilon)-(2-[(18)F]fluoropropionyl)-Lys(0)-Tyr(3)-octreotate ([(18)F]FP-Gluc-TOCA) was completed in approximately 3 h (20%-30% yield). [(19)F]FP-Gluc-TOCA showed no affinity to hsst1 and hsst3, moderate affinity to hsst4 (IC(50): 437+/-84 n M) and hsst5 (IC(50): 123+/-8.8 n M) and very high affinity to hsst2 (IC(50): 2.8+/-0.4 n M). As a result of carbohydration, lipophilicity of [(18)F]FP-Gluc-TOCA was found to be low (lg P(OW)=-1.70+/-0.02). In mice, the tracer was rapidly cleared via renal excretion (kidneys: 8.69%+/-1.09%ID/g) and showed low uptake in liver (0.72%+/-0.14%ID/g) and intestine (1.88%+/-0.52%ID/g) and high tumour uptake (13.54%+/-1.47%ID/g) (all data at 1 h p.i.). Tumour to non-tumour ratios at 60 min p.i. reached 25, 19, 7, 1.6 and 56 for blood, liver, intestine, kidney and muscle, respectively. A similar biodistribution pattern was observed in pancreatic tumour-bearing rats. Tumour uptake in rats was reduced to 36% and 18% of control (30 and 60 min) by co-injection of 500 microg Tyr(3)-octreotide, demonstrating sst-specific uptake. In a first [(18)F]FP-Gluc-TOCA-PET study of a patient with a metastatic carcinoid in the liver the tracer showed superior pharmacokinetics, e.g. rapid urinary excretion and low uptake in liver, kidney and spleen. Multiple liver lesions (SUVs ranging from 21.4 to 38.0) and previously unknown focal uptake in the abdomen (SUV 10.0) were clearly visible. This is the first report on PET imaging using an (18)F-labelled sst binding peptide; it indicates that [(18)F]FP-Gluc-TOCA offers excellent imaging characteristics and allows sst imaging with high tumour to non-tumour contrast.

Aged↗
PubMed2001

Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography.

The alpha(v)beta3 integrin is an important cell adhesion receptor involved in tumor-induced angiogenesis and tumor metastasis. Here we describe the 18F-labeling of the RGD-containing glycopeptide cyclo(-Arg-Gly-Asp-D-Phe-Lys(sugar amino acid)-) with 4-nitrophenyl 2-[18F]fluoropropionate and the evaluation of this compound in vitro and in tumor mouse models. Binding assays with isolated immobilized alpha(v)beta3, alpha(v)beta5, and alpha(IIb)beta3 as well as in vivo studies using alpha(v)beta3-positive and -negative murine and xenotransplanted human tumors demonstrated receptor-specific binding of the radiolabeled glycopeptide yielding high tumor:background ratios (e.g., 120 min postinjection: tumor:blood, 27.5; tumor:muscle, 10.2). First imaging results using a small animal positron emission tomograph suggest that this compound is suitable for noninvasive determination of the alpha(v)beta3 integrin status and therapy monitoring.

Animals↗
PubMed2001

Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics.

UNLABELLED: The alpha(v)beta3 integrin plays an important role in metastasis and tumor-induced angiogenesis. Targeting with radiolabeled ligands of the alpha(v)beta3 integrin may provide information about the receptor status and enable specific therapeutic planning. Previous studies from our group resulted in tracers that showed alpha(v)beta3-selective tumor uptake. However, these first-generation compounds predominantly revealed hepatobiliary excretion with high radioactivity found in the liver. In this report, the synthesis and biological evaluation of the first glycosylated RGD-containing peptide (RGD-peptide) for the noninvasive imaging of alpha(v)beta3 expression are described. METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl-coupling protocols. The precursor cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP1 was synthesized by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-beta-D-glycero-D-gulo-heptonic acid (SAA(Bn3)) with cyclo(-Arg(Mtr)-Gly-Asp(OtBu)-D-Tyr(tBu)-Lys-) and subsequent removal of the protection groups. Iodine labeling was performed by the Iodo-Gen method (radiochemical yield > 50%). The in vitro binding assays were performed using purified immobilized alpha(IIb)beta3, alpha(v)beta5, and alpha(v)beta3 integrins. For in vivo experiments, nude mice bearing xenotransplanted melanomas and mice with osteosarcomas were used. RESULTS: The glycosylated peptide 3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP2 showed high affinity and selectivity for alpha(v)beta3 in vitro (50% inhibitory concentration = 40 nmol/L). Pretreatment studies indicate specific binding of [125I]GP2 on alpha(v)beta3-expressing tumors in vivo. Comparison of the pharmacokinetics of [125I]GP2 and [125I]-3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) [125I]P2 revealed for [125I]GP2 an increased activity concentration in the blood (e.g., 3.59 +/- 0.35 percentage injected dose [%ID]/g vs. 1.72 +/- 0.44 %ID/g at 10 min postinjection) and a significantly reduced uptake in the liver (e.g., 2.59 +/- 0.24 %ID/g vs. 21.96 +/- 2.78 %ID/g at 10 min postinjection). Furthermore, a clearly increased activity accumulation in the tumor was found (e.g., 3.05 +/- 0.31 %ID/g vs. 0.92 +/- 0.16 %ID/g at 240 min postinjection), which remained almost constant between 60 and 240 min postinjection. This resulted in good tumor-to-organ ratios for the glycosylated tracer (e.g., 240-min postinjection osteosarcoma model: tumor-to-blood = 16; tumor-to-muscle = 7; tumor-to-liver = 2.5), which were confirmed by the first gamma-camera images of osteosarcoma-bearing mice at 240 min postinjection. CONCLUSION: This study demonstrates that the introduction of a sugar moiety improves the pharmakokinetic behavior of a hydrophobic peptide-based tracer. Additionally, this alpha(v)beta3-selective glycosylated radioiodinated second-generation tracer GP2 shows high tumor uptake and good tumor-to-organ ratios that allow noninvasive visualization of alpha(v)beta3-expressing tumors and monitoring therapy with alpha(v)beta3 antagonists. Finally, the favorable biokinetics make the glycosylated RGD-peptide a promising lead structure for tracers to quantify the alpha(v)beta3 expression using PET.

Animals↗
PubMed2001

Tumor angiogenesis targeting using imaging agents.

The inhibition of tumor induced angiogenesis is an emerging therapeutic strategy in clinical oncology aimed at halting cancer progression by suppressing tumor blood supply. As anti-angiogenic therapy is primarily cytostatic and not cytotoxic, the established criteria for assessing tumor response to chemo- and radiotherapy cannot be applied to anti-angiogenic therapy. Therefore, functional and molecular parameters for imaging of tumor angiogenesis are being intensively studied. Computed tomography, magnetic resonance imaging, ultrasound and scintigraphic techniques can assess changes in vascular permeability and tumor blood flow during anti-angiogenic therapy. Scintigraphic techniques, especially positron emission tomography (PET), may be used to monitor the consequences of anti-angiogenic therapy on tumor cell metabolism, proliferation and apoptosis. The high sensitivity of PET which allows measurements of tracer concentrations in the picomolar range is promising for the visualization of specific molecular targets prior to therapy thus identifying patients most likely benefit from a particular form of anti-angiogenic therapy.

Angiogenesis Inhibitors↗
PubMed2000

O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study.

O-(2-[18F]Fluoroethyl)-L-tyrosine (FET) is a recently described amino acid analogue that has shown high accumulation in animal tumours. The aim of this study was to compare the uptake of FET with that of L-[methyl-11C]methionine (MET) in patients with suspected primary or recurrent intracerebral tumours. Sixteen consecutive patients with intracerebral lesions were studied on the same day by positron emission tomography (PET) using MET and FET. Uptake of FET and MET was quantified by standardized uptake values. Tracer kinetics for normal brain and intracerebral lesions were compared. On the basis of the MET-PET studies, viable tumour tissue was found in 13 patients. All tumours showed rapid uptake of FET and were visualized with high contrast. Mean uptake of FET for normal grey matter, white matter and tumour tissue was 1.1+/-0.2, 0.8+/-0.2 and 2.7+/-0.8 SUV, respectively. In all three tissues, uptake of MET was slightly higher (1.4+/-0.2, 0.9+/-0.1 and 3.3+/-1.0 SUV; P<0.01). However, contrast between tumour and normal tissues was not significantly different between MET and FET. Uptake of FET in non-neoplastic lesions (1.0+/-0.1 SUV) was significantly lower than in tumour tissue (P = 0.007). For all lesions there was a close correlation (r = 0.98) between MET and FET uptake. In conclusion, in PET studies of human brain tumours, the uptake and image contrast of FET appear to be very similar to those of MET. The specificity of FET for tumour tissue is promising but has to be addressed in a larger series of patients with non-neoplastic lesions.

Adult↗
PubMed2000

6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine ([18F]DPN): synthesis, biologic evaluation, and comparison with [11C]DPN in humans.

UNLABELLED: 6-O(2-[18F]fluoroethyl)-6- -desmethyldiprenorphine ([18F]DPN) was developed and biologically evaluated. Results of animal experiments, binding studies in vivo, and a human PET study are reported and compared with those of [11C]DPN. METHODS: [18F]DPN was obtained by 18F-fluoroethylation of 3-O-trityl-6-O-desmethyldiprenorphine and subsequent deprotection in good radiochemical yields (23% +/- 7%; 100 min; 37 TBq/mmol). Binding of [18F]DPN to mu, kappa, and delta opioid receptors was shown by autoradiography studies on rat brain slices. Quantification of cerebral opioid receptor binding in men was performed by spectral analysis of a dynamic PET scan (25 frames, 90 min) after intravenous application of 63 MBq [18F]DPN (36 GBq/micromol) and correction for metabolites. RESULTS: [18F]DPN shows high affinity to opioid receptors. Parametric images (impulse response function at 60 min) of this human study showed a binding pattern of [18F]DPN equal to that of a control group (n = 9 healthy volunteers) after administration of [11C]DPN. CONCLUSION: The advantage of the longer half-life of 18F will allow extended scanning periods, more flexible interventions (e.g., displacement studies), and DPN to be available to PET centers without an on-site cyclotron.

Adult↗
PubMed2000

Phantom limb pain in the human brain: unraveling neural circuitries of phantom limb sensations using positron emission tomography.

Pain and other phantom limb (PL) sensations have been proposed to be generated in the brain and to be reflected in activation of specific neural circuits. To test this hypothesis, hypnosis was used as a cognitive tool to alternate between the sensation of PL movement and pain in 8 amputees. Brain activity was measured using positron emission tomography. PL movement and pain were represented by a propagation of neuronal activity within the corresponding sensorimotor and pain-processing networks. The sensation of movement was significantly (corrected for multiple comparisons) related to activity in the supplementary motor area and the primary sensorimotor cortex. The sensation of a painful PL posture activated the same brain areas but was weaker and less extended in the supplementary motor area. In contrast to the sensation of movement, pain was significantly related to activity in the thalamus, anterior cingulate, and lateral prefrontal cortex. Subjectively rated PL pain sensation correlated positively to activations in the anterior and posterior cingulate. These findings provide evidence that PL sensations are produced by the same central nervous processes that underlie the experience of the body when it is intact and that the corporeal awareness of PL pain is encoded in a thalamocortical network.

Adult↗
PubMed1999

Opioid receptors in the human cerebellum: evidence from [11C]diprenorphine PET, mRNA expression and autoradiography.

Little is known regarding opioid receptors in the human cerebellum. The present [11C]diprenorphine PET study investigated opioid receptor binding in the human cerebellum in vivo, and showed a differential binding level in cerebellar cortex, vermis and dentate nuclei. The additional study in vitro of opioid receptors in human cerebellar cortex and rat brain corroborated the presence of opioidergic mechanisms in the human cerebellum in contrast to the rat. A differential cellular distribution pattern was detected for the three major opioid receptors investigated. For the mu-receptor, and at a lower level for the kappa-receptor, mRNA expression was mainly observed over granule cells. Binding sites were most prominent in the molecular layer. For the delta-receptor no signal was detected. The consideration of cerebellar opioidergic mechanisms and the distribution patterns of the various opioid receptors may promote the understanding of cerebellar function and of opioidergic pharmacology in the human.

Adult↗
PubMed1999

Preclinical evaluation of 4-[18F]fluoroprolines: diastereomeric effect on metabolism and uptake in mice.

The aim of this study was to evaluate the diastereomeric effect on uptake and metabolic behavior of (2S,4R)-4-[18F]fluoro-L-proline (trans-[18F]FPro) and (2S,4S)-4-[18F]fluoro-L-proline (cis-[18F]FPro) in view of their potential suitability as tracers for abnormal collagen synthesis. No-carrier-added 4-[18F]fluoro-L-prolines were prepared according to the literature in about 150 min (50-60% radiochemical yield). Both compounds exhibited high in vivo stability. The tumor uptake of cis-[18F]FPro in osteosarcomas of mice was high and at 240 min postinjection reached 11.8 +/- 2.2 %ID/g compared with 7.07 +/- 1.68 %ID/g for trans-[18F]FPro. In contrat to trans-[18F]FPro, which showed fast and complete renal clearance, the cis isomer was accumulated in the pancreas, and showed hepatic clearance and renal reuptake. Speciation studies on tissue homogenates revealed protein incorporation only for cis-[18F]FPro. However, due to the relatively slow protein incorporation rate of cis-[18F]FPro, the tumor uptake of both compounds in colon carcinomas, mammary carcinomas, and osteosarcomas 1 h postinjection predominantly reflect amino acid transport.

Animals↗
PubMed1999

Central pain after pontine infarction is associated with changes in opioid receptor binding: a PET study with 11C-diprenorphine.

Using 18F-fluorodeoxyglucose and 11C-diprenorphine positron emission tomography (PET), we investigated alterations in glucose metabolism and opioid receptor binding in a patient with central poststroke pain, which developed after a small pontine hemorrhagic infarction. In comparison with normal databases, reduced 11C-diprenorphine binding was more accentuated than the hypometabolism on the lateral cortical surface contralateral to the symptoms, and a differential abnormal distribution between the tracers was seen in pain-related central structures. These results show that 11C-diprenorphine PET provides unique information for the understanding of central poststroke pain.

Adult↗
PubMed1999

Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo.

UNLABELLED: The aim of the study was to investigate the transport mechanism and uptake kinetics of the new 18F-labeled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (L-[18F]FET) and D-[18F]FET in human SW 707 colon carcinoma cells and the in vivo biodistribution of this tracer in SW 707 tumor-bearing mice. METHODS: SW 707 cells were incubated with L- and D-[18F]FET under physiologic amino acid concentrations with and without the competitive transport inhibitors 2-amino-2 norbornane-carboxylic acid and a-(methylamino)isobutyric acid plus serine. For the investigation of the transport capacity, unlabeled L-FET was added to the samples. In addition, xenotransplanted mice were injected intravenously with L-[18F]FET; killed 10, 30, 60 and 120 min after injection; and the radioactivity concentration in different organs was measured in a gamma counter. RESULTS: The in vitro kinetic experiments showed a fast initial uptake of L-[18F]FET into the cells up to 6 min, followed by a nearly constant tracer concentration. The accumulation factor, calculated as the ratio between intracellular and extracellular tracer concentration, ranged from 3.0 to 5.0. In comparison, D-[18F]FET did not accumulate in the cells. Washing the cells in medium at 37 degrees C, after a 30-min incubation with L-[F-18]FET, led to a rapid decrease of radioactivity, which demonstrates the bidirectional transport. In addition, experiments with increasing concentrations of unlabeled L-FET indicated a linear correlation between L-FET uptake rate and the extracellular concentration. Results of transport inhibition experiments with the specific competitive inhibitors demonstrated that the uptake of L-FET into SW 707 cells was caused mainly (>80%) by the transport system L. In the in vivo studies, the half-life (t1/2 beta) of L-[18F]FET in the plasma was determined to be 94 min and the uptake into the brain increased to 120 min with a brain-to-blood ratio of 0.86. The xenotransplanted tumor showed higher uptake of L-[18F]FET (>6 %ID/g) at 30 and 60 min than all other organs, except the pancreas. The tumor-to-blood ratio reached about 2 between 30 and 120 min. CONCLUSION: L-[18F]FET, which is transported by the specific amino acid transport system L, seems to be a potential amino acid tracer for tumor imaging and therapy monitoring with PET.

Animals↗
PubMed1999

Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting.

UNLABELLED: The alpha(v)beta3 integrins play an important role during tumor metastasis and tumor-induced angiogenesis. Targeting of this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Cyclo(-Arg-Gly-Asp-D-Phe-Val-) has been shown to be a selective alpha(v)beta3 integrin antagonist with high affinity. In this study we describe the synthesis and biological evaluation of [125I]-3-iodo-D-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) ([125I]P2), [125I]-3-iodo-Tyr5-cyclo(-Arg-Gly-Asp-D-Phe-Tyr-) ([125I]P4) and the negative control peptide [1251]-3-iodo-D-Tyr4-cyclo(-Arg-D-Ala-Asp-Tyr-Val-) ([125I]P6). METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl amino acid coupling protocols. Radioiodination was performed using the iodogen method. The in vitro binding assays were performed using isolated, immobilized alphaIIbeta3 and alpha(v)beta3 integrins. Expression of the alphaVbeta3 receptor on the different tumors was validated by immunohistochemical methods using alpha(v) and alpha(v)beta3 specific antibodies. For biodistribution studies, nude mice with melanoma M21 or mammary carcinoma MaCaF and BALB/c mice with osteosarcoma were used. RESULTS: The in vitro binding assays demonstrate that the introduction of tyrosine and subsequent iodination have no influence on the high affinity and selectivity for alpha(v)beta3. Immunohistochemical staining clearly indicates the presence of the alpha(v)beta3 integrins on the tumor tissue of the melanoma and the osteosarcoma. Pretreatment and displacement studies show specific binding of [125I]P2 on melanoma M21-bearing nude mice and osteosarcoma-bearing BALB/c mice but less specific binding on mammary carcinomas. [125I]P2 exhibits fast elimination kinetics. The accumulation in the tumor 10 min postinjection is 2.07 +/- 0.32 %ID/g for the melanoma M21 and 3.50 +/- 0.49 %ID/g for the osteosarcoma and decreases to 1.30 +/- 0.13 %ID/g and 2.03 +/- 0.49 %ID/g 60 min postinjection, respectively. [125I]P4 shows even faster elimination kinetics, resulting in a tumor accumulation of 0.40 +/- 0.10 %ID/g 60 min postinjection for the osteosarcoma-bearing BALB/c mice. Both peptides reveal predominately hepatobiliary excretion. For [1251]P2, this also is confirmed by autoradiography. The negative control peptide [125I]P6 shows no specific activity accumulation. CONCLUSION: [125I]P2 exhibits high affinity and selectivity for the alpha(v)beta3 integrin in vitro and in vivo and, thus, represents the first radiolabeled alpha(v)beta3 antagonist for the investigation of angiogenesis and metastasis in vivo.

Animals↗
PubMed1999

Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging.

UNLABELLED: The aim of the study was to develop a simple 18F-labeled amino acid as a PET tracer for cerebral and peripheral tumors. O-(2-[18F]fluoroethyl)-L-tyrosine (L-[18F]FET) was synthesized and biologically evaluated. Results of the first human PET study are reported. METHODS: No carrier added (n.c.a.) and D-[18F]FET were prepared by 18F-fluoroethylation of L- and D-tyrosine in a two-step procedure. Biodistribution studies were performed in mice. The metabolic fate of L-[18F]FET was investigated in plasma, brain, tumor and pancreatic tissue samples using chromatographic procedures. Tumor uptake studies were performed in mammary carcinoma-bearing mice and in mice with the colon carcinoma SW 707. In a human PET study, a 59-y-old man with a recurrent astrocytoma was imaged using n.c.a. L-[18F]FET. RESULTS: Synthesis of [18F]FET was accomplished in about 50 min with an overall radiochemical yield of 40%. The uptake of L-[18F]FET in the brain of mice reached a level >2% ID/g between 30 and 60 min postinjection. The brain uptake of the D-isomer was negligible, indicating blood-brain barrier penetration by a specific amino acid transport system. L-[18F]FET is not incorporated into proteins. High-performance liquid chromatography (HPLC) analysis of brain, pancreas and tumor homogenates as well as plasma samples of mice at 10, 40 or 60 min postinjection showed only unchanged L-[18F]FET. Activity uptake in the bone did not exceed 2% ID/g at 40 min postinjection. The brain uptake of L-[18F]FET in mice bearing mammary carcinomas and colon carcinomas reached 7.1%+/-1.2% ID/g and 6.4%+/-1.7% ID/g 1h postinjection, respectively. In the first human study, L-[18F]FET-PET allowed a clear delineation of a recurrent astrocytoma. Thirty-five minutes postinjection, the tumor-to-cortex ratio was >2.7. A tumor-to-blood ratio >1.5 was reached at 30 min postinjection and continued to increase. No significant activity accumulation was observed in peripheral organs after approximately 40 min postinjection. CONCLUSION: The high in vivo stability of L-[18F]FET, its fast brain and tumor uptake kinetics, its low accumulation in nontumor tissue and its ease of synthesis strongly support further evaluation of L-[18F]FET as an amino acid tracer for cerebral and peripheral tumors.

Animals↗