In this study, we have calculated and reported the pharmacokinetics of irinotecan and its active metabolite, SN-38, in patients with increased plasma bilirubin levels. Four patients suffering from metastatic colorectal cancer (CRC) with high bilirubin levels (0.7 to 15 mg/dl) were selected for our study. These patients were being treated by CPT -11 (Irinotecan) in the hospital setup. To all four patients, CPT-11 was administered as a 60 min IV- infusion (180 mg/m2, total dose 339 ± 32 mg). Blood samples were collected at 0, 15, 30, 45, 60, 90,120, 180, 240, 300 and 360 minutes after the drug administration. The drug and its pharmacologically active metabolite, SN38 were quantified in these samples by an HPLC method. The blood level profiles were analyzed for their PK behavior by Kinetica® software system. SN 38 levels were found to be decreasing with increasing bilirubin values. The possible rationalizing for lower SN38 levels with elevated bilirubin levels might be some liver impairment which slows the metabolic conversion of irinotecan into SN-38.

Aim: Capecitabine, a 5-fluorouracil prodrug, has been integrated into the management of multiple cancer types. In order to obtain information about plasma levels of capecitabine in patients who had drug intake at home during chemotherapy, a simple HPLC method for capecitabine monitoring has been developed and validated. Patients and Methods: Capecitabine levels were quantified by a simple reversed-phase HPLC system with an external standard method. Plasma samples were obtained from 12 colorectal cancer patients who underwent chemotherapy with capecitabine alone (1000 mg/m(2)) or combined with oxaliplatin (130 mg/m(2)). Results: Although there was evidence that capecitabine had not been taken according to the chemotherapeutic schedule in two cases, the study demonstrated that its combination with oxaliplatin showed no significant drug drug interactions. Conclusion: Due to its robustness, specificity and sensitivity, the method is also well-suited for capecitabine analysis in other pharmacokinetic studies.

Since to date very limited information on the distribution and function of the adenosine A 3 receptor is available, the development of a suitable radioligand is needed. Such a selective radioligand can then be used for quantitative autoradiography, preclinical studies in animals and subsequent human PET applications. Recently, a promising candidate compound, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY), has been presented. The successful preparation of a suitable labelling precursor and the evaluation and optimization of the radiosynthesis of [ 18 F] FE@SUPPY is presented herewith. For satisfactory yields, a reaction temperature of 75 °C has to be applied for at least 20 min using 8–10 mg of precursor. Until now, 15 complete high-scale radiosyntheses were performed. Starting from an average of 51±12 GBq (average ±SD; range: 30–67 GBq) [ 18 F]fluoride, 9.4–3.6 GBq of formulated [ 18 F]FE@SUPPY (32.3±12.4%, based on [ 18 F]fluoride, corrected for decay) were prepared in <105 min.

Since to date very limited information on the distribution and function of the adenosine A(3) receptor is available, the development of a suitable radioligand is needed. Such a selective radioligand can then be used for quantitative autoradiography, preclinical studies in animals and subsequent human PET applications. Recently, a promising candidate compound, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY), has been presented. The successful preparation of a suitable labelling precursor and the evaluation and optimization of the radiosynthesis of [F-18] FE@SUPPY is presented herewith. For satisfactory yields, a reaction temperature of 75 degrees C has to be applied for at least 20 min using 8-10 mg of precursor. Until now, 15 complete high-scale radiosyntheses were performed. Starting from an average of 51 +/- 12 GBq (average +/- SD; range: 30-67 GBq) [F-18]fluoride, 9.4 +/- 3.6 GBq of formulated [F-18]FE@SUPPY (32.3 +/- 12.4%, based on [(18)]fluoride, corrected for decay) were prepared in < 105 min.

Purpose: Since the late 1980s, cocaine analogues based on the phenyltropane structure, such as [C-11]CFT and [I-123]beta-CIT have been used for the imaging of the dopamine transporter. FE@CIT (fluoropropyl ester) and FP-CIT (N-fluoropropyl derivative) are further analogues. The aim of this study was to (1) evaluate and compare the metabolic stability of beta-CIT, FP-CIT and FE@CIT against carboxyl esterases and (2) evaluate selectivity of [F-18]FE@CIT compared to [I-123]beta-CIT and [I-123]FP-CIT using autoradiography.Methods: In vitro enzymatic hydrolysis assays were performed using different concentrations of beta-CIT, FE@CIT and FP-CIT with constant concentrations of carboxyl esterase. Autoradiography was performed on coronal 20-mu m rat brain sections incubated with different radioactivity concentrations of [I-123]beta-CIT, [123 I]FP-CIT or [F-18]FE@CIT and, additionally, with 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [serotonin transporter (SERT)] and nisoxetine [norepinephrine transporter (NET)] for blocking experiments.Results: In vitro assays showed Michaelis-Menten constants of 175 mu mol (beta-CIT), 183 mu mol (FE@CIT) and 521 mu mol (FP-CIT). Limiting velocities were 0.1005 mu mol/min (beta-CIT), 0.1418 mu mol/min (FE@CIT) and 0.1308 mu mol/min (FP-CIT). This indicates a significantly increased stability of FP-CIT, whereas carboxyl esterase stability of beta-CIT and FE@CIT showed no significant difference. Autoradiographic analyses revealed a good correlation between dopamine transporter (DAT)-rich regions and the uptake pattern of FE@CIT. Blocking experiments showed a higher DAT selectivity for [F-18]FE@CIT than for the other two tracers.Conclusion: We found that (1) the metabolic stability of FE@CIT was comparable to that of beta-CIT, whereas FP-CIT showed higher resistance to enzymatic hydrolysis; and (2) the overall uptake pattern of [F-18]FE@CIT on brain slices was comparable to that of[I-123]beta-CIT and [I-123]FPCIT. After blocking of NET and SERT binding, a significantly higher DAT selectivity was observed for [F-18]FE@CIT. Hence, [F-18]FE@CIT may be of interest for further clinical application. (C) 2008 Elsevier Inc. All rights reserved.

Introduction: Changes of the adenosine A(3) receptor subtype (A3AR) expression have been shown in a variety of pathologies, especially neurological and affective disorders, cardiac diseases and oncological and inflammation processes. Recently, 5-(2-fluoroethyl) 2,4-diethyl-3(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY) was presented as a high-affinity ligand for the A3AR with good selectivity. Our aims were the development of a suitable labeling precursor, the establishment of a reliable radiosynthesis for the fluorine-(18)-labeled analogue [F-18]FE@SUPPY and a first evaluation of [F-18]FE@SUPPY in rats.Methods: [F-18]FE@SUPPY was prepared in a feasible and reliable manner by radiofluorination of the corresponding tosylated precursor. Biodistribution was carried out in rats, and organs were removed and counted. Autoradiography was performed on rat brain slices in the presence or absence of 2-Cl-IB-MECA.Results: Overall yields and radiochemical purity were sufficient for further preclinical and clinical applications. The uptake pattern of [F-18] FE@SUPPY found in rats mainly followed the described mRNA distribution pattern of the A3AR. Specific uptake in brain was demonstrated by blocking with a selective A3AR agonist.Conclusion: We conclude that [F-18]FE@SUPPY has the potential to serve as the first positron emission tomography tracer for the A3AR. (C) 2008 Elsevier Inc. All rights reserved.

PET imaging of the μ-opioid receptor (OR) is still restricted to [11C]carfentanil ([11C]CFN) but its use is limited due to its short half-life and high agonistic potency. Recently, the radiosynthesis of [18F]fluoroalkyl esters of CFN was proposed, unfortunately yielding products not suitable for human PET due to their low specific activities. Therefore, our rationale was to develop a reliable radiosynthesis of a [18F]fluoroethylated CFN derivative overcoming these drawbacks. The [18F]fluoroethyl ester of carfentanil, [18F]FE@CFN (2-[18F]fluoroethyl 4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate), and its corresponding inactive standard compound were prepared. Purification of [18F]FE@CFN was achieved via a simple solid phase extraction method. [18F]FE@CFN was prepared with excellent purity (> 98%) and sufficient yields. Specific activity surpassed the level required for safe administration. We therefore conclude that our simplified synthesis of [18F]FE@CFN, for the first time, overcomes the shortcomings of [11C]CFN and the previously suggested alternatives, namely, (1) longer half-life; (2) easy production and (3) adequate specific activity, should make a wider application possible. Hence, [18F]FE@CFN may become a valuable PET tracer for the imaging of the μ-OR in human brain and heart.

Introduction: The objectives of this study were to develop a simple preparation method for [Ga-68]-EDTMP and to evaluate the applicability of [Ga-68]-EDTMP as a potential positron emission tomography (PET) bone imaging agent using pre vivo, ex vivo and in vivo models. Methods: [Ga-68]-EDTMP was prepared using [Ga-68]-gallium chloride eluted from the Ge-68/6(8G)a generator and commercially available Multibone kits. Binding affinity to bone compartments was evaluated using a recently established pre vivo model. In vivo (microPET) and ex vivo experiments were performed in mice, and the results of which were compared with those obtained with [F-18]-fluoride. Results: [Ga-68]-EDTMP was accessible via simple kit preparation and predominantly accumulated in bone tissue in vivo, ex vivo and pre vivo. Binding to mineral bone was irreversible, and low binding was observed in organic bone. In vivo microPET evaluation revealed predominant uptake in bone with renal excretion. Compared with [F-18]-fluoride, the uptake was lower and the PET image quality was reduced. Conclusions: From the present evaluation, apart from the autonomy for PET centers without an onsite cyclotron, the advantage of [Ga-68]EDTMP over [F-18]-fluoride is not apparent and the future clinical prospect of [Ga-68]-EDTMP remains speculative. (c) 2007 Elsevier Inc. All rights reserved.

So far, [carbonyl-11C]WAY-100635 is the PET-tracer of choice for 5HT1A-receptor-imaging. Since the preparation is still a challenge, we aimed at (1) the evaluation of various essential parameters for the successful preparation, (2) the simplification of the radiosynthesis and (3) the establishment of a safe and fully automated system. The preparation is based on a commercial synthesizer and all chemicals are used without further processing. We found a low failure rate (7.7%), high average yield (4.0 ± 1.0 GBq) and a specific radioactivity of 292 ± 168 GBq/μmol (both at the end of synthesis, EOS).

Introduction: The translation of C-11-labeled compounds into their respective F-18-labeled derivatives is an important toot in the rapid development of positron emission tomography (PET) tracers. Thus, our aim was the development of a general method for the preparation of F-18-fluoroethylated compounds that (a) is applicable to a variety of precursors, (b) can be performed in a fully automated commercially available synthesizer and (c) enables this rapid translation of C-methylated tracers into their F-18-fluoroethylated analogs sharing the same precursor molecules.Methods: Ten methods for the preparation and purification of different F-18-fluoroethylating agents were compared. Subsequently, five F-18-labeled PET tracers were synthesized under fully automated conditions.Results: Radiochemical yields ranged from 34.4% to 60.8%, and time consumption ranged from 20 to 55 min for all methods. Use of 1-bromo-2-[F-18]fluoroethane and distillation evinced as the method of choice.Conclusions: We were able to develop a general method for the preparation of a variety of F-18-fluoroethylated molecules. The provided tool is solely based on commercially available resources and has the potential to simplify and accelerate innovative PET tracer development in the future. (c) 2007 Elsevier Inc. All rights reserved.

11β-Hydroxylase is a key enzyme in the biosynthesis of adrenocortical steroid hormones and is a suitable target for the imaging of the adrenal cortex. [11C]Metomidate (MTO), [11C]etomidate (ETO) and desethyl-[18F]fluoroethyl-etomidate (FETO) are potent inhibitors of this enzyme and are used for PET imaging of adrenocortical pathologies. The aims of this study were (1) to evaluate and compare the metabolic stability of MTO, ETO and FETO against esterases and (2) to investigate the metabolic pattern of FETO in vivo.

The present study focused on the preparation of novel bone tracers containing yttrium as radionuclide or carrier. Moreover, these preparations were comparatively evaluated in vitro on the basis of a recently presented pre vivo model comprising binding studies on synthetic and human bone powder. It was shown that among the therapeutic radionuclides, no carrier added [(90)Y]-EDTMP exceeded [(188)Re]-EDTMP while yielding lower binding values than [(153)Sm]-EDTMP. Furthermore, the authors investigated the influence of "foreign" carriers added to [(90)Y]-EDTMP, [(99m)Tc]-EDTMP and [(111)In]-EDTMP by the method of cross-complexation. The findings reveal a new paradigm: a carrier more foreign to the complexed radionuclide causes a higher binding increase on human bone matrices in vitro than a more "related" carrier.

Although polyphosphonates (PPs) were introduced as bone imaging agents in nuclear medicine in the early 1970s, the mechanisms involved in their uptake still remain unclear. Suggested mechanisms range from mineral adsorption with disputed binding to the organic phase, over incorporation into the mineralisation process to a combination of both mechanisms. Thus, our investigations aimed to: (1) evaluate adsorption parameters of 99mTc-MDP, 153Sm-EDTMP and 18F-fluoride on mineralising osteoblast cultures, (2) correlate the radiotracer binding measured in the cell cultures with binding values from our previously presented mineral model and (3) compare binding with cell number.

Functional imaging of the adrenal cortex by means of PET may play an important clinical role. Recently, we presented the synthesis and first evaluation of a novel 11β-hydroxylase inhibitor, [18F]FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [18F]FETO as a PET tracer for the adrenal cortex in humans.

Background: The present study was designed to investigate whether a combination of irinotecan and the monoclonal antibody cetuximab shows potential to modulate the pharmacokinetics of irinotecan and its metabolites. Patients and Methods: All patients, suffering from advanced colorectal cancer, received irinotecan (350 mg/m(2)) every third week and cetuximab as a loading dose (400 mg/m(2)) on day 2, followed by a weekly maintenance dose (250 mg/m(2)). Plasma samples were analysed after the first (MONO) and second (CMAB) irinotecan infusions. Results: No significant alterations in the plasma concentrations and pharmacokinetics of irinotecan and its metabolites were observed after combination with cetuximab. Only differentiation of irinotecan into lactone and carboxylate plasma concentrations resulted in a distinctly lower c(max) of the active lactone in the CMAB and a significant higher AUC(last) in the MONO schedule (p < 0.02). Conclusion: The results of this study indicated that cetuximab has no clinically relevant impact on the pharmacokinetics of irinotecan, its activation into SN-38, or its detoxification by beta-D-glucuronidation.

Nucleophilic aromatic substitution is a challenging task in radiochemistry. Therefore, a thorough evaluation and optimisation of this step is needed to provide a satisfactory tool for the routine preparation of [(18)F]fluorinated aromatic amino acids. Two methods, already proposed elsewhere, were evaluated and improved. The yields for the radiofluorination were increased whereas activity loss during solid phase extraction was observed. Radiochemical yields for the two methods were 92.7+/-5.5% (method 1) and 92.1+/-12.3% (method 2) for conversion and 11.1+/-2.8% (method 1) and 34.8+/-0.6% (method 2) for purification, respectively. In total, we demonstrate an optimised method for the preparation of this important class of [(18)F]fluorinated synthons for PET.