H.-J. Machulla

Metabolism of 15 (p123I iodophenyl-)pentadecanoic acid in heart muscle and noncardiac tissues

The uptake and turnover of ω(p123I iodophenyl-) pentadecanoic acid (I-PPA), a radioiodinated free-fatty-acid analog, was examined in the heart, lung, liver, kidneys, spleen, and skeletal muscle of rats. At 2 min post injection, a high cardiac uptake of 4.4% dose per gram had already been achieved; this was followed by a rapid, two-component, tracer clearance. The kinetics of tissue concentrations of labeled hydrophilic catabolites indicated a rapid oxidation of I-PPA and the subsequent washout of I-PPA catabolites from heart-muscle tissue. The fractional distribution of the labeled cardiac lipids compared favorably with previously reported values for 3H-oleic-or 14C-palmitic-acid-labeled myocardial lipids. Typical patterns of I-PPA metabolism were observed in tissues depending on primary fatty-acid oxidation, lipid metabolism regulation, or I-PPA-catabolite excretion. The tissue concentrations and kinetics of I-PPA and its metabolites in the heart muscle indicated that general pathways of cardiac-lipid metabolism are traced by this new γ-emitting isotope-labeled radiopharmaceutical.

Assessment of PET Tracer Uptake in Hormone-Independent and Hormone-Dependent Xenograft Prostate Cancer Mouse Models

The pharmacokinetics of 18F-fluorodeoxythymidine (FLT), 18F-FDG, 11C-choline, and 18F-fluoroethylcholine (FEC) in 2 hormone-independent (PC-3, DU145) and 2 hormone-dependent (CWR22, PAC120) prostate cancer xenograft mouse models were evaluated by PET and compared by immunohistochemistry. Further investigation was performed to determine whether PET can detect early changes in tumor metabolism after androgen ablation therapy through surgical castration. Methods: PET was performed on 4 consecutive days. In addition, the CWR22 and PAC120 tumor models were surgically castrated after the baseline measurement and imaged again after castration. The tracer uptake was analyzed using time–activity curves, percentage injected dose per volume (%ID/cm3), and tumor-to-muscle ratio (T/M). Results: Regarding the hormone-independent prostate tumor models, 18F-FLT showed the best T/M and highest %ID/cm3 in PC-3 (2.97 ± 0.63 %ID/cm3) and DU145 (2.06 ± 0.75 %ID/cm3) tumors. 18F-FDG seemed to be the tracer of choice for delineation of the PC-3 tumors but not for the DU145 tumors. Using 11C-choline (PC-3: 1.33 ± 0.29 %ID/cm3, DU145: 1.60 ± 0.27 %ID/cm3) and 18F-FEC, we did not find any significant uptake in the tumors, compared with muscle tissue. Regarding the hormone-dependent prostate tumor models, the CWR22 model showed a highly significant (P < 0.01) decrease in tumor 18F-FDG uptake from 4.11 ± 1.29 %ID/cm3 to 2.19 ± 1.45 %ID/cm3 after androgen ablation therapy. However, the 18F-FLT, 11C-choline, or 18F-FEC tracers did not provide sufficient uptake or reliable information about therapy response in CWR22 tumors. The PAC120 model showed a significant increase in 18F-FLT tumor uptake (P = 0.015) after androgen ablation therapy. The accumulation of 18F-FEC (before: 2.32 ± 1.01 %ID/cm3, after: 1.36 ± 0.39 %ID/cm3) was found to be the next highest after 18F-FDG (before: 2.45 ± 0.93 %ID/cm3, after: 2.18 ± 0.65 %ID/cm3) in PAC120 tumors before castration and is better suited for monitoring therapy response. Conclusion: This comprehensive study in 2 hormone-dependent and 2 hormone-independent prostate tumor mouse models shows that 18F-FLT and 18F-FDG are the most appropriate tracers for delineation of PC-3, DU145 (except 18F-FDG), and CWR22 tumors, but not for PAC120 tumors. 18F-FEC and 11C-choline, in particular, revealed insufficient T/M ratio in the prostate tumor models. The results may indicate that radiolabeled choline and choline derivatives compete with a high concentration of the precursor dimethylaminoethanol, resulting in reduced uptake in small-rodent tumor models, a hypothesis that is currently under investigation in our laboratory.

Automated synthesis of n.c.a. [18F]FDOPA via nucleophilic aromatic substitution with [18F]fluoride.

An improved, automated synthesis of [(18)F]FDOPA including four synthetic steps (fluorination, reductive iodination, alkylation and hydrolysis) is reported with each step optimized individually. In a home-made automatic synthesizer, 9064+/-3076 MBq of [(18)F]FDOPA were produced within 120 min from EOB (n=5). Radiochemical purity and enantiomeric excess were both >or= 95%. Specific activity was ca. 50 GBq/micromol at EOS. This automatically operable synthesis is well suited for the multi-patient-dose routine production of n.c.a. [(18)F]FDOPA.

Radiosynthesis of carbon-11 labeled 6-methyldopamine ([11C]MeDA)

A rapid and efficient n.c.a. radiosynthesis of 6-[(11)C]methyldopamine ([(11)C]MeDA) using the Stille cross-coupling reaction as a key step was developed. The labeling conditions for the formation of the intermediate compound (protected [(11)C]MeDA, [(11)C]7) were determined with respect to reaction temperature and time. The radiochemical yield 89 ± 1.4% (decay-corrected) of the protected intermediate [(11)C]7 was obtained at a reaction temperature of 60°C and a reaction time of 5 min using Pd(2)(dba)(3)/P(o-tolyl)(3) and CsF/CuBr as a co-catalyst system. The overall yield after deprotection with 45% HBr at 140°C for 10 min was 64 ± 3.9% (decay-corrected) within a total preparation time of 40 min, including hydrolysis, HPLC purification and formulation.

Comparative evaluation of labelling patterns and turnover of lipids, tagged by 15 /p-123I-phenyl-/ pentadecanoic and 1-14C-palmitic acid

Uptake and turnover of chloroform/methanol extractable tissue lipids labelled in vivo simultaneously with 15/p-123I-phenyl-/pentadecanoic and l-14C-palmitic acid were compared. Lipid turnover studies were performed in fasted pentobarbital-anaesthetized Wistar rats in tissues with highly varying free fatty acid turnover rates. In all tissues investigated, i.e. heart, lung, liver, spleen and kidneys, both tracers labelled nearly identical lipid fraction. Main tracer uptake was found in free fatty acids, phospholipids, diglycerides and triglycerides. A highly significant correlation of uptake and turnover in main tissue lipid fraction indicated an essentially identical metabolic pathway of both tracers in intermediary tissue lipid metabolism. Concordant tracer uptake and turnover patterns in tissue of lipids with highly varying free fatty acid metabolic rates suggested that intrinsic metabolic activity of the tissue and respective lipid fraction was the major determinant of metabolic handling of both iodophenyl fatty- and palmitic acid. Thus, the feasibility of iodophenylpentadecanoic acid as free fatty acid tracer for studying tissue lipid metabolism is demonstrated.