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This study was set up to demonstrate whether prognostic classification based on the secondary age-adjusted International Prognostic Index (sAA-IPI) for recurring aggressive non-Hodgkin lymphoma (NHL) or the prognostic score for recurring Hodgkin lymphoma (HL) can be improved by including the midtreatment results of fluorine-18-fluorodeoxy-glucose-positron emission tomography (FDG-PET). Clinical data on patients with recurring lymphoma who were treated with second-line chemotherapy (DHAP-VIM-DHAP) followed by autologous stem cell transplantation (ASCT) were collected and combined with the results of FDG-PET performed before and after 2 cycles of reinduction chemotherapy. PET responses after 2 courses were scored as complete remission (CR), partial remission (PR), or no response (NR). A multivariate analysis was performed to design a predictive model. The number of patients (101 of 117) included those (78 patients with aggressive NHL and 23 patients with HL) that could be analyzed according to protocol. Of these, 80 patients were chemosensitive and 77 received transplants. Both secondary clinical risk score (P<.001) and FDG-PET response (P<.001) were independent predictive factors for the total evaluable group of patients with lymphoma and for patients with NHL alone. The combined use of the clinical risk score and FDG-PET response after 2 chemotherapy courses identified at least 4 categories of patients with a failure-free survival varying between 5% to 100% after transplantation (P<.001). These data indicate that the secondary clinical risk score in conjunction with FDG-PET response provides a more accurate prognostic instrument for the outcome of second-line treatment at least in patients with recurring NHL.

Objectives: Positron emission tomography (PET) scanning may provide information on changes in the density and affinity of airway beta-adrenoceptors in lung diseases. However, the injection of a radiolabeled beta-blocker results in a pulmonary PET signal that reflects the binding of the ligand in the alveoli and not in the airways. Better discrimination between alveolar and airway beta-adrenoceptors may be possible with an inhaled radioligand., Design: A nebulizer was used to administer the antagonist S-11C-CGP12388 in aerosol form. Eight volunteers inhaled the tracer twice, at baseline and after pretreatment with a beta-adrenergic drug. In both PET scan studies, a dynamic scan of the lungs was followed by a whole-body scan to assess the inhaled dose. Pulmonary uptake was quantified using a region-of-interest-based analysis., Setting: University hospital., Participants: Healthy volunteers., Interventions: Pretreatment consisted either of inhaled salbutamol (400 microg, 20 min before the scan), or orally administered pindolol (3 x 5 mg during a period of 16 h before PET scanning)., Results: Drug pretreatment did not affect pulmonary deposition of the radioligand. The agonist salbutamol accelerated the monoexponential washout of 11C not only in the peripheral lung (mainly alveoli), but also in the central lung (mainly airways) and in the main bronchi. An even larger increase of the washout rate was induced by the antagonist pindolol., Conclusion: The similar effects of pindolol and salbutamol on tracer kinetics suggest that accelerated washout is due to the blockade of beta-adrenoceptors. Thus, the interaction of drugs with airway beta-adrenoceptors can be visualized using PET scanning and an inhaled radioligand.

Inducible NO synthase (iNOS) is overexpressed in inflammatory bowel diseases. An antisense oligonucleotide with good hybridization properties for iNOS mRNA was selected using RT-PCR. The oligonucleotide was reliably labeled with fluorine-18 using N-(4-[(18)F]fluorobenzyl)-2-bromoacetamide. Cellular uptake and efflux of oligonucleotide complexed with FuGENE-6 were rapid, unlike naked oligonucleotide, which hardly accumulated. However, neither uptake nor efflux showed any selectivity for iNOS expressing cells. The oligonucleotide showed a high level of non-specific binding, which may have obscured its specific hybridization to iNOS mRNA.

Background: Sarcomas represent a significant diagnostic and therapeutic challenge that requires techniques to provide better assessment of the disease than provided by traditional means. FDG-PET depicts the increased metabolism in abnormal tissues, enabling visualisation and quantification in vivo. The objective of this review was to assess the diagnostic value of FDG-PET in the detection, grading and therapy response of soft tissue and bone sarcomas., Methods: A systematic review and meta-analysis of clinical studies on FDG-PET and sarcomas was conducted. Databases of PubMed, Embase and Cochrane were searched for studies. Besides that, the references of identified studies were reviewed. Three reviewers independently assessed the methodological quality. Statistical pooling was possible for studies concerning detection and grading of studies with mixed sarcomas (soft tissue and bone) and studies with soft tissue sarcomas only., Results: Twenty-nine studies met the inclusion criteria. There was disagreement between the reviewers in 21.5% of the questions from the criteria list. The methodological quality of most of the included studies was poor. Pooled sensitivity, specificity and accuracy of PET for the detection of sarcomas were 0.91, 0.85 and 0.88, respectively. The difference between the mean Standard Uptake Value (SUV) in malignant and benign tumours for the studies concerning mixed and soft tissue sarcomas was statistically significant, as well as the difference in FDG uptake between low and high grade mixed sarcomas., Conclusions: The meta-analysis in this study was limited by the fact that only a few studies had mutual comparable outcome parameters. Moreover, the methodological quality of the studies was generally poor. Nevertheless, our results indicate that FDG-PET can discriminate between sarcomas and benign tumours and low and high grade sarcomas based on the mean SUV. The diagnostic implications of these results have to be investigated, especially the discrimination between benign tumours and low grade sarcomas. Based on this meta-analysis, there is no indication to use FDG-PET in the standard treatment of sarcomas. In the future PET imaging in bone and soft tissue sarcomas should be directed to the clinical implication for the detection and grading of sarcomas and the treatment evaluation of locally advanced sarcomas.

In rats, the relationship between [(18)F]FHPG accumulation and HSVtk expression was studied with PET and autoradiography. [(18)F]FHPG distribution closely corresponded with HSVtk immunohistochemical staining. ROI analysis of tracer uptake 2 hours p.i. and Patlak graphical analysis were applied to quantify the PET data. For both analysis methods, the [(18)F]FHPG PET signal correlated well with the fraction of HSVtk expressing cells implanted, but showed a plateau when plotted against HSVtk protein levels. This might be due to rate limiting [(18)F]FHPG membrane transport.

We prepared sigma(1)-receptor selective 1-([4-methoxy-(11)C]-3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([(11)C]SA4503) and its fluorinated analog 1-([4-methoxy-(11)C]3,4-dimethoxyphenethyl)-4-[3-(4-fluorophenyl)propyl]piperazine ([(11)C]SA5845), and their [(11)C]ethoxy and [(18)F]fluoroethoxy analogs, and evaluated their potential for positron emission tomography studies. [(11)C]SA4503 is most selective for sigma(1) receptors, and the other five showed affinities for sigma(1) and sigma(2) receptors with a different extent. All radioligands showed the receptor-specific binding in the brain, and visualized similar regional brain distributions by ex vivo autoradiography. The [(11)C]ethoxy analogs were relatively labile for metabolism.

The efficacy of chemotherapy for malignant primary or metastatic brain tumours is still poor. This is at least partly due to the presence of the blood-brain barrier (BBB). The functionality of the BBB can be explained by physicochemical features and efflux pump mechanisms. An overview of the literature is presented with emphasis on oncology. The BBB consists of capillary endothelial cells that lack fenestrations and are connected together with continuous tight junctions, with a high electrical resistance. Permeability of tight junctions can be increased in vitro by contraction of the cytoskeleton, caused by bradykinin agonists. Different efflux pumps are present in the BBB. Examples are P-glycoprotein (P-gp), organic anion transporters, (OAT) and multidrug-resistance-associated proteins (MRP)(1 and 3). These pumps act as a multi-specific efflux pump for various chemotherapeutic drugs. Experiments have shown that P-gp can be inhibited by different non-chemotherapeutic substrates such as cyclosporin A. The functionality in vivo of P-gp can be measured with positron emission tomography and [(11)C]-verapamil or with single photon emission computer tomography and(99m)Tc-sestamibi. MRP(1)and MRP(3)act as organic anion transporters that in vitro act as efflux pumps for substances that are conjugated or co-transported with glutathione and glucuronide, respectively. Methotrexate has been recently demonstrated to be transported by MRP(1)and MRP(3). Results of studies which demonstrate the clinical relevance and applicability of BBB modulators are eagerly awaited., (Copyright 2000 Harcourt Publishers Ltd.)

Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido+ ++] ethylpiperazine ([(18)F]p-MPPF) can be used for 5-hydroxytryptamine(1A) (5-HT(1A)) receptor imaging. The aim of this study was to develop a method for the quantitative imaging of 5-HT(1A) receptors in healthy volunteers with [(18)F]p-MPPF. After injection of [(18)F]p-MPPF radioactivity was rapidly taken up in the brain, with the highest accumulation in the medial temporal cortex. Low levels of radioactivity were found in cerebellum and basal ganglia. Plasma clearance and metabolism of [(18)F]p-MPPF resulted in only about 1% of the radioactivity in plasma as parent radioligand after 10 min. Using a linear graphical method (Logan-Patlak), binding potentials were calculated in several brain areas. A good correlation (r = 0.95) was found between the obtained binding potentials and literature values for 5-HT(1A) receptor densities. A good correlation (r = 0.96) was also found between the body weight-corrected region/cerebellum ratios and the respective binding potentials. Moreover, a blocking experiment with pindolol (n = 3) showed a decrease of 40% in the region/cerebellum ratios of the target areas. Compared to those of [carbonyl-(11)C]WAY-100635, the binding potentials were four to six times lower, indicating that [(18)F]p-MPPF has a lower in vivo affinity for 5-HT(1A) receptors. In conclusion, [(18)F]p-MPPF can be used for the quantitative analysis of 5-HT(1A) receptor distribution in human brain.

S-1'[(18)F]-Fluorocarazolol (FCAR) is a fluorinated analog of the nonmutagenic beta-blocker carazolol (CAR). In former studies FCAR proved to be suitable for quantification of beta-adrenoceptors in vivo with positron emission tomography (PET). We report here that FCAR displays no acute toxicity in either rats or mice. However, FCAR induces a strong dose-related increase in the number of revertants in the Ames test. We conclude that FCAR yields mutagenic activity as measured by the Ames test.

[(11)C]-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([(11)C]FMAU) and [(18)F]-9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG), radiolabeled representatives of two classes of antiviral agents, were evaluated as tracers for measuring herpes simplex virus thymidine kinase (HSV-tk) enzyme activity after gene transfer and as tracers for localization of active human cytomegalovirus (HCMV) infections. In vitro accumulation experiments revealed that both [(11)C]FMAU and [(18)F]FHPG accumulated significantly more in HSV-tk expressing cells than they did in control cells. [(18)F]FHPG uptake in HSV-tk expressing cells, however, was found to depend strongly on the cell line used, which might be due to cell type dependent membrane transport or cell type dependent substrate specific susceptibility of the enzyme. In vitro, both tracers exhibited a good selectivity for accumulation in HCMV-infected human umbilical vein endothelial cells over uninfected cells. In contrast to [(18)F]FHPG, [(11)C]FMAU uptake in control cells was relatively high due to phosphorylation of the tracer by host kinases. Therefore, [(18)F]FHPG appears to be the more selective tracer not only to predict HSV-tk gene therapy outcome, but also to localize active HCMV infections with PET.

Myocardial and pulmonary beta-adrenoceptors can be imaged with 2-(S)-(-)-(9H-carbazol-4-yl-oxy)-3-[1-(fluoromethyl)ethyl]amino-2- propanol (S-1'-[18F]fluorocarazolol, I). Quantification of unmodified fluorocarazolol in plasma is necessary for analysis of PET images in terms of receptor densities. We have determined I and its radioactive metabolites in rat, sheep and human plasma, using (1) solid-phase extraction (C18) followed by reversed-phase HPLC and (2) direct injection of untreated plasma samples on an internal-surface reversed-phase (ISRP) column. The two methods were in good agreement. Unmodified I decreased from over 99% initially to less than 5%, 5-10% and 20% at 60 min post-injection in rats, sheep and human volunteers, respectively. Protein binding in sheep and human plasma was determined by ultrafiltration. The fraction of total plasma radioactivity bound to protein and the fraction representing unmodified radioligand were linearly correlated, suggesting that fluorocarazolol was more than 70% protein-bound, whereas its metabolites showed negligible protein binding. Direct injection of plasma on an ISRP column seems a convenient method for quantification of lipophilic radioligands such as fluorocarazolol.

The beta-adrenoceptor antagonist carazolol has been labelled with fluorine-18 in the isopropyl group via a reductive alkylation by [18F]-fluoroacetone of the corresponding (S)-desisopropyl compound according to a known procedure. The introduction of fluorine in the isopropyl group creates a new stereogenic centre resulting in the formation of (S,S)- and (S,R)-1'-[18F]fluorocarazolol, which were separated by HPLC. Tissue distribution studies were performed in male Wistar rats. Both the (S,S)- and (S,R)-diastereomers (S.A. 500-2000 Ci/mmol; 18.5-74 TBq/mmol) showed high uptake in lung and heart, which could be blocked by pretreatment of the animals with (+/-)-propranolol. No significant differences were observed between the biodistribution of the two diastereomers. Metabolite analysis showed a rapid appearance of polar metabolites in plasma, while at 60 min postinjection 92% and 82% of the total radioactivity in lung and heart was unmetabolized 1'-[18F]fluorocarazolol. In a PET-study with male Wistar rats, the lungs were clearly visualized and the pulmonary uptake was decreased after pretreatment of the animals with (+/-)-propranolol. The heart could not be visualized. Similar results were obtained in PET-studies with lambs.

N-Isopropylnorephedrine (INE) and N-fluoroisopropylnorephedrine (FINE) were found to have a poor affinity for either beta-adrenoceptors and the norepinephrine carrier protein. The low affinity of both compounds for Uptake-1 is probably due to the introduction of a bulky substituent on the nitrogen atom. It is concluded that INE and FINE cannot be used for cardiac imaging with PET.

beta-Adrenoceptors in human lungs and heart can be imaged with the radioligand 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3- dihydro-2H-benzimidazol-2-11C-one (CGP 12177, [11C]I). For quantification of receptor density with compartment models by adjustment of rate constants, an 'input function' is required which consists of the integral of the concentration of unmodified ligand in arterial plasma over time. A discrepancy in the literature regarding metabolic stability of [11C]I prompted us to study metabolism in rats by reversed-phase HPLC (RP-HPLC) of trichloroacetic acid extracts of arterial plasma after i.v. injection of [11C]I (> 11.1 TBq/mmol, 11 MBq/kg). Some plasma samples were also directly applied to an internal-surface reversed-phase (ISRP) column. In parallel experiments, tritiated [11C]I was employed and methanol extracts of arterial plasma were analyzed by straight-phase TLC. The three methods were in excellent agreement. Unmodified [11C]I decreased from > 98.5% (3H) or > 99.9% (11C) initially to 57 +/- 7% at 80 min post injection due to formation of two polar metabolites. Using the RP-HPLC method, no metabolism was detectable in humans up to 30 min after injection of [11C]I (1851 MBq). Deproteinization of plasma with acetonitrile resulted in the formation of a radioactive species (artifact) which eluted immediately after the void volume in RP-HPLC and which could be mistakenly interpreted as a metabolite. Plasma protein binding was low (ca. 30%) in both humans and rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of estrogen receptors and progesterone receptors (PR) with PET may allow the determination of the hormone responsiveness of tumors without the need for multiple biopsies, and the monitoring of the effect of hormonal therapy. In spite of the favourable characteristics of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone ([18F]FENP) found in preclinical studies, the compound failed to reveal the presence of PR in breast carcinomas and meningiomas. In view of the clinical significance of the PR assay in human breast cancer, it is worthwhile to explore mechanisms that are potentially involved in the inadequacy of [18F]FENP to image PR with PET. Our present study on the in vivo metabolism of [18F]FENP in humans demonstrates a rapid clearance and biotransformation of the compound. Results of incubation experiments suggest that the metabolic conversion of [18F]FENP is not restricted to the liver, but also occurs in blood cells (presumably the erythrocytes) and tumors (breast carcinomas and meningiomas). The predominant metabolite of [18F]FENP in plasma during the rapid distribution phase and in tumors is identified as 20-dihydro-[18F]FENP. The conversion of [18F]FENP to its 20 alpha- or 20 beta-hydroxy metabolite has a deleterious effect on the binding affinity for PR. Our findings do not justify a conclusion as to the extent of in vivo extrahepatic biotransformation of [18F]FENP, or its significance in the ineffectiveness of [18F]FENP as an imaging agent for PR. On the other hand, the ability of breast carcinomas and meningiomas to metabolize [18F]FENP avidly appears to preclude selective imaging of PR in these tumors during the time of a PET examination. It is imperative to evaluate the metabolic stability of a [18F]fluorine labeled progestin in an early stage of future screening procedures.

The most selective beta 1-adrenoceptor ligand known at this moment is (S)-1-[2-((carbamoyl-4-hydroxy) phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-2-propanol (CGP 26505), the S-isomer of CGP 20712A. We prepared the racemic 11C analogue by methylation with [11C]CH3I of the corresponding desmethyl compound using a microwave oven to accelerate the reaction. Several radioactive by-products (about 70% of the non-volatile radioactive products) were formed. After HPLC purification [11C]CGP 20712A with a specific activity of 35 TBq/mmol was dissolved in a propylene glycol-ethanol-saline mixture to prepare it for injection. The total preparation time was 35 min. The radiochemical yield was 5% (calculated from [11C]CH3I, not corrected for decay). The identity of [11C]CGP 20712A was proved by liquid chromatography-mass spectrometry (LC-MS). Tissue distribution studies in male Wistar rats have been performed. At 20 min after injection of the radioligand (0.1 nmol) the DAR [differential absorption ratio = (counts per minute recovered/g tissue)/(counts per min injected/g body weight)] in heart tissue decreased significantly (P < 0.005) from 1.84 +/- 0.11 to 1.21 +/- 0.12 after blocking of beta-adrenoceptors with 500 micrograms (R,S)-propranolol. A preliminary PET study in a Wistar rat showed maximal uptake in the time frame 10-20 min after injection. The ratio of specific/non-specific binding at this interval was 2.6.

The biodistribution of [3H]4-DAMP (a M3-selective cholinoceptor antagonist) was studied in rats which had received either saline or saline containing atropine (to block cholinoceptors). Specific binding of the radioligand was observed in the urinary bladder, ileum, pancreas, stomach, submandibular gland and trachea. Maximal ratios of total-to-non-specific uptake reached values of 1.8 (trachea), 3.2 (bladder), 4.0 (stomach), 4.8 (ileum), 6.6 (pancreas) and 6.9 (submandibular gland) at 5-10 min post-injection; this rank order reflects the tissue densities of M3 cholinoceptors, 4-DAMP did not bind to blood cells and it was rapidly cleared from the circulation (> 90% with a half-life of 0.2 min, the remainder with a half-life of 9.4 min). Labelled metabolites appeared within 5 min in plasma, but metabolite uptake by the target organs was low (< 15% of total radioactivity 40 min post-injection). Although 4-DAMP binds to M3-cholinoceptors in vivo, its potential use as a radiopharmaceutical appears limited since the compound does not cross the blood-brain barrier and it does not show measurable specific binding in airways.

(+/-)-1'-[18F]Fluorometoprol 4 was prepared from desisopropylmetoprolol and [18F]fluoroisopropyl tosylate 2 with a radiochemical yield of 2% [corrected for decay to end of bombardment (EOB), synthesis time 90 min]. Synthon 2 was prepared from (S)-1,2-propanediol di(p-toluenesulfonate) in 45% radiochemical yield (EOB, 40 min). Compound 4 shows in two in vitro assays a similar affinity at beta-adrenoceptors (about 0.3 microM) as metoprolol 5, but with a slightly higher beta 1/beta 2-adrenoceptor selectivity ratio (48.6 vs 30.7). In vivo experiments with 4 showed almost no receptor-mediated uptake in the heart, probably because the affinity of (fluoro)metoprolol for the beta 1-adrenoceptors is too low for successful imaging. However, the in vitro experiments suggest that the fluoroisopropyl group is suitable for the synthesis of [18F]fluorinated beta 1-adrenergic receptor binding ligands.

A method for the rapid production and purification of 10,11-dihydroxy-N-([11C]methyl)norapomorphine ([11C]APO), a dopamine agonist (DA), is described. The potency of this ligand for studying the D2-receptors was examined. The label was introduced by N-methylation of norapomorphine hydrobromide with no-carrier-added (n.c.a) [11C]CH3I, produced from cyclotron-produced [11C]carbon dioxide. In 60 min (EOB) a radiochemical yield of 15% (corrected for decay) was achieved, based on [11C]CH3I. The specific activity ranged from 5 to 11 GBq/mumol. The distribution, after intravenous injection, was studied in rats. The radioactivity level in the striatum was higher than in the cerebellum and frontal cortex and was decreased after D2-blockade. The highest uptake ratio (1.47) was found at 30 min after injection. Dopamine depletion with reserpine did increase the striatum/cerebellum ratio at a low dosage of [11C]APO (10 nmol/kg). High uptakes of [11C]apomorphine were found in the lungs, liver and kidneys.

We investigated whether the lack of therapeutic response to long-term and adequate neuroleptic treatment was due to a failure to achieve a blockade of cerebral dopamine receptors. Six chronic schizophrenic and medicated patients (DSM-III-R diagnosis, paranoid or disorganized type) were assessed with the Present State Examination and the Brief Psychiatric Rating Scale. According to the Chouinard Rating Scale there were little extrapyramidal symptoms, although no anticholinergic drugs were given. Plasma levels of the neuroleptics were determined and found in the therapeutic range or higher. Dopamine D2-receptor occupancy was determined with positron emission tomography using 11C-methylspiperone as ligand. There was a more than 95% blockade of the D2 receptors in the striatum. These results indicate that the lack of therapeutic response and extra-pyramidal side effects cannot be attributed to an incomplete blockade of cerebral D2 receptors and that the pathogenetic role of these receptors can be questioned in therapy-resistant schizophrenic patients.

In 13 hemiparkinson patients possible changes in dopamine receptors were investigated in vivo with PET, using [11C]methylspiperone as the receptor labeling ligand. Though in individual patients the specific binding of the tracer differed between both striata, no consistent difference was found. However, the specific binding in the striatum of patients with longterm dopaminergic medication was significantly higher than in non-medicated patients, and close to normal. No correlation with the predominantly unilateral clinical pathology was found. Since the postsynaptic receptor changes in hemiparkinson patients appear not to be uniform, these results suggest that the clinical asymmetry is not only caused by a dysfunction of nigral dopaminergic cells, but by pathology in other cells and probably in other neurotransmitter systems as well. The observed bilateral increase in receptor binding during dopaminergic therapy most likely results from a symmetrical change in local pharmacokinetics or from alteration of the receptor binding. Further studies with PET are needed to determine the exact nature of this change.