Gerhard Stöcklin

Radiopharmaceuticals for Positron Emission Tomography

General guidelines for the quality assurance and quality control of short-lived radiophannaceuticals for positron emission tomography (pE1) are given. Quality assurance and quality control recommendations are also given for aselection of frequently used short-lived radiophannaceuticals for PET, namely [t-1 1C]acetate, S-[carbonyl-llC]CGP 12177, L-[N-methyP1C]deprenyl, [N-methyt-11C]flumazenil, lIC-labelled-L-methionines, 3-N -[ l1C]methylspiperone, [O-methyP1C]raclopride, [13N]ammonia, 150-labelled gases, n-[150]butanol, [ISO]water, [18F]fluoride, 2-[I8F]fluoro-2deoxy-D-glucose, L-6-[18F]fluoro-OOPA and 18F-labelled 3-N-alkylspiperones.

(2-[18F]fluoropropionyl-(d)phe1)-octreotide, a potential radiopharmaceutical for quantitative somatostatin receptor imaging with PET: Synthesis, radiolabeling, in vitro validation and biodistribution in mice

Octreotide is labeled with fluorine-18 as a potential radiopharmaceutical for quantitative in vivo mapping of somatostatin receptors. [18F]-fluoroacylation is achieved with n.c.a. 2-[18F]fluoropropionic acid 4-nitrophenylester which is reacted with epsilon-Boc-Lys5-octreotide. After deprotection the desired N alpha-[18F]fluoropropionylated octreotide ([18F]SDZ 223-228) is obtained. Final HPLC purification gives rise to radiochemical yields of 65 +/- 5% based on the fluoroacylation agent. Binding experiments using rat cortex membranes indicate an affinity for somatostatin receptors of pKi = 8.6 +/- 0.2. The biological activity of this SRIF analog is demonstrated by the inhibition of growth hormone release from cultured pituitary cells. The pIC50 in this test system is 8.75, indicating full biological activity. Biodistribution studies with NMRI mice show predominantly renal excretion, rapid blood clearance and only negligible bone activity, i.e. formation of free fluoride.

Fluoroacylation agents based on small n.c.a. [18F]fluorocarboxylic acids

Abstract Three methods for fluoroacylation of amines are compared using 2-[ 18 F]fluoroaliphatic acyl moieties as small prosthetic groups. [ 18 F]fluoroacetic and -propionic acid alkylesters are common intermediates for all three methods and obtained with > 90% radiochemical yields. They can directly be used for fluoroacylation of primary amines. In the second method the free [ 18 F]fluoroaliphatic acid is condensed with amines using dicyclohexyl carbodiimide (DCC). However, formation of byproducts limits the radiochemical yield to about 60%. Alternatively imidazolides or p -nitrophenyl and succinimidyl esters were prepared. Fluoroacylation yields with these highly activated esters exceed 90% in organic solvents. Fluoroacylation of dipeptides in aqueous solution proceeds with a yield of 70–80%. N -succinimidyl 4-[ 18 F]fluorobenzoate was also prepared with a 3-fold higher radiochemical yield (75%) than reported earlier.

Production of the Positron Emitting Radioisotope 86Y for Nuclear Medical Application

The production of 86Y via the 86Sr(p,n)-reaction was studied. Samples of 96.3% enriched 86SrCO3 were irradiated using a 4 π water-cooled target system at nearly optimum proton energy ranges (14 → 10 MeV) at beam currents of 3–8 μA. Thick target yields calculated from the measured excitation functions were compared with results from production runs. A chemical separation procedure including the recovery of the enriched target material was developed. Activities of about 1.5 GBq (40 mCi) 86Y per batch with high radionuclidic and radiochemical purity were achieved and [86Y]citrate was prepared for pharmacokinetic studies using PET.

Radiation doses of yttrium-90 citrate and yttrium-90 EDTMP as determined via analogous yttrium-86 complexes and positron emission tomography

Yttrium-90 is used for palliative therapy for the treatment of skeletal metastases, but because it is a pure β- emitter, data on the pharmacokinetics and radiation doses to metastases and unaffected organs are lacking. To obtain such data, the present study employed yttrium-86 as a substitute for90Y, with detection by positron emission tomography (PET). The study compared the properties of two different86Y complexes —86y-citrate and86Y -ethylene diamine tetramethylene phosphonate (EDTMP) — in ten patients with prostatic cancer who had developed multiple bone metastases (the ten patients being divided into two groups of five). Early dynamics were measured up to 1 h post injection (p.i.) over the liver region, followed by subsequent whole-body PET scans up to 3 days p.i. Absolute uptake data were determined for normal bone, bone metastases, liver and kidney. Radiation doses were calculated according to the MIRD recommendations. Based on the pharmacokinetic measurements of the distribution of the86Y complexes, it was possible to calculate radiation doses for the bone metastases and the red bone marrow delivered by complexes containing90Y. In 1 cm3 of bone metastasis, doses of 26±11 mGy/MBq and 18±2 mGy/MBq were determined per MBq of injected90Y- citrate and90Y- EDTMP, respectively. The doses to the bone marrow were 2.5±0.4 mGy/MBq for90Y- citrate and 1.8±0.6 mGy/MBq for90Y-EDTMP.86Y and PET provide quantitative information applicable to the clinical use of90Y. This method may also be useful for the design of other90Y radiopharmaceuticals and for planning radiotherapy dosages.

PET-pharmacokinetics of 18F-octreotide: A comparison with 67Ga-DFO and 86Y-DTPA-octreotide

The quantitative uptake kinetics of (2-[18F]fluoropropionyl-(D)phe1)-octreotide (I), a somatostatin (SRIF) receptor-specific tracer, was measured by PET. Conventional organ biodistribution and in vivo stabilities of the tracer as well as in vivo displacement and SRIF receptor blocking were determined. The 18F-fluorinated octreotide was compared with ([67Ga]-DFO-B-succinyl-(D)phe1)-octreotide (II) and ([86Y]-DTPA-(D)phe1)-octreotide (III). Initially, 2-10 MBq of the labeled tracers were injected into male Lewis rats bearing an exocrine pancreatic islet cell tumor. PET measurements were performed dynamically between 0 and 120 min postinjection. Organ distributions were determined 5, 15, 30, 60, and 120 min postinjection. The extent of metabolic degradation was analyzed in serial blood and urine samples as well as in homogenized samples of tumor, liver, and kidney. The uptake of (I) by the tumor was rapid (maximum accumulation at 1-2 min postinjection) and high (about 0.5 +/- 0.2% ID/g), followed by a fast and continuous release with koff = 10 +/- 2. 10(-5) s-1. The tracer was found to remain intact in vivo up to 120 min postinjection. Specific binding of (I) to SRIF receptors in the adrenals, the pancreas, and the pituitary gland was demonstrated in vivo by pretreatment and displacement experiments. Compound (II) also showed a fast uptake by the tumor. Its tumor residence half-life was longer (koff = 3.0 +/- 0.5 . 10(-5) s-1). Compound (II) was also predominantly excreted intact. One hour postinjection, the remaining activity in the blood pool was found to be bound to serum proteins. Early uptake kinetics for compound (III) were also rapid but reached only half the tumor uptake of (II). Compared to (I), the release of 86Y-activity from the tumor was slower (koff = 3.1 +/- 1.3 . 10(-5) s-1). Compared to (II), compound (III) was considerably less stable in vivo. The main critical organs for (II) and (III) are kidneys and bones, whereas (I) is predominantly accumulated in the liver. The in vivo behavior of (I) closely resembles 14C-labeled octreotide. Thus, 18F-labeled octreotide may be of interest in the quantitation and investigation of in vivo properties of somatostatin receptors by PET. However, the short residence of (2-[18F]fluoropropionyl-(D)phe1)-octreotide in tumors and its hepatobiliary excretion may complicate the interpretation of abdominal tumors.

PET measurement of D2 and S2 receptor binding of 3-N-([2′-18F]fluoroethyl)spiperone in baboon brain

The regional pharmacokinetic behavior in baboon brain of 18F-fluoroethyl-and 18F-fluoropropylspiperone (18FESP, 18FPSP) at specific activities≥1000 Ci/mmol was studied with PET. Four hours after injection of 5–10 mCi 18FESP, uptake in striatum was 0.048%±0.005% of injected dose per cm3, which is almost the same as with 18F-and 11C-methylspiperone. While 18FPSP was taken up in much smaller amounts than 18FESP, striatum to cerebellum activity ratios were quite similar for both ligands (about 9 to 10 at 4 h p.i.). Because of its higher striatal uptake, 18FESP seems to be better suited for PET. Furthermore, relative binding to S2 receptors was much smaller for FESP: competing cold S2 antagonists (ritanserin, ketanserin) did not alter 18FESP binding to striatum, concurrently reducing uptake in frontal cortex by only 15%–20%. With coninjection of increasing amounts of cold FESP, saturation of 18FESP binding to striatum occurred at doses exceeding 10 μg per kg. Quantitative analysis of radiolabelled ligand in arterial plasma (decrease to 8% at 4 h p.i.) demonstrated identical metabolic turnover for both ligands. Direct use of binding fractions from the saturation curve resulted in overestimation of the receptor density in striatum. Using the 18FESP plasma concentration time curve and the dynamic uptake data, k3 of a three compartment model could be determined by non linear regression. However, dramatic changes of the dependence of k3 on the specifically bound ligand concentration were observed even at small loading doses of FESP. Estimation of Bmax yielded a D2 receptor density of only 6 pmol per cm3 in baboon striatum.

Direct electrophilic radiofluorination of phenylalanine, tyrosine and dopa

Abstract The reactivity and selectivity of [ 18 F]F 2 and [ 18 F]AcOF with aromatic amino acids in various solvents were compared. An HPLC method based on ion pair chromatography was developed allowing the isocratic separation of all fluoroisomers of phenylalanine, tyrosine and dopa with a single column. While AcOF exhibited a higher regioselectivity and less side product formation, practical labelling yields were higher with [ 18 F]F 2 . In CF 3 CO 2 H as solvent the preferentially formed isomers 2-[ 18 F]fluorophenylalanine, 3-[ 18 F]fluorotyrosine and 2-[ 18 F]fluorodopa were obtained in good yields of 20, 28 and 7.5%, respectively. After O-acetylation of tyrosine, 2-[ 18 F]fluorotyrosine was obtained with a radiochemical yield of 16% by direct fluorination with [ 18 F]AcOF followed by hydrolysis. In all cases the pure l -isomer was obtained.

PET studies of dopamine receptor distribution using [18F]fluoroethylspiperone: findings in disorders related to the dopaminergic system

PET studies of dopamine D2-receptor binding were performed in thirty patients with various disorders related to the dopaminergic system and in six healthy controls. Uptake of [18F]fluoroethylspiperone in caudate over three hours was analyzed in terms of several indices of receptor binding: caudateto-cerebellum activity ratio, concentration of ligand as percentage of injected dose, caudate-to-blood radioactivity ratio, slope of tracer uptake curves, binding potential, kinetic constants of a three compartment model. In 14 patients brain glucose metabolism was also measured. Data on medicated patients demonstrate that the average values of most of the above parameters indicate the decreased number of available D2-receptors whereby, besides an age dependent decline, the caudate-to-cerebellum ratio affords the relatively best distinction among diagnostic groups. In individual cases, large variability among subjects permits only the classification of severe pathologies. Morphological damage and neuronal loss in the striatum may also cause abnormal low values both for the indices of receptor binding and for glucose consumption, thus providing a possible pathogenetic link between receptor dysfunction and impaired energy metabolism.

Direct n.c.a. electrophilic radioiodination of tyrosine analogues; their in vivo stability and brain-uptake in mice

In order to improve tracers for amino acid transport studies with SPET we have radioiodinated methylated tyrosines and compared their brain uptake and in vivo deiodination in mice. O-methylation not only leads to a higher lipophilicity and hence significantly higher brain uptake with a maximum of 5% dose/g for 3-[123I]iodo-O-methyl-L-alpha-methyltyrosine (OMIMT) but also significantly prevents in vivo deiodination. High n.c.a. radioiodination yields (> or = 80%) are obtained for the activated aromatic compounds L-tyrosine and L-alpha-methyltyrosine using Iodo-gen iin a heterogeneous aqueous system. Direct n.c.a. radioiodination of the less-activated O-methyl analogues has been achieved in reasonable yields (60%) with Iodo-gen in homogeneous TFA solutions containing about 10% of water.