Verlag des Forschungszentrums Jülich
JUEL-3602
For the determination of the pharmacokinetics of [1-11C]acetate in porcine myocardium
during prolonged ischemia, n.c.a. [1-11C]acetate was synthesized via carboxylation
of methylmagnesium bromide with in target produced n.c.a. [11C]CO2 with a
radiochemical yield (RCY) of 68 ± 7 %. The fast (18 min) and reliable radiosynthesis
allowed for repeated tracer administration at short intervals (< 20 min).
In order to study the pharmacokinetics and metabolism of acetylsalicylic acid
(Aspirin®) in humans, [1-11C]acetylsalicylic acid, acetyl-[carboxy-11C]salicylic
acid and [carboxy-11C]salicylic acid were prepared. N.c.a. [1-11C]acetylsalicylic
acid was synthesized via the reaction of [1-11C]acetylchloride with salicylic
acid salts. The use of the silver salt proved to be superior to the sodium salt
and resulted in radiochemical yields of 32 ± 5 %. Base-line (clean) separation
of the labelled product was achieved using radio-HPLC.
With regard to the preparation of n.c.a. [carboxy-11C]salicylic acid, several
protected and unprotected phenol derivates were metallated and subsequently
carboxylated using n.c.a. [11C]CO2. Best results (87 ± 3 % RCY) could be achieved
with 2-(methoxymethoxy)-phenylmagnesium iodide as a precursor and subsequent
quantitative cleavage of the MOM-group. Acetylation of n.c.a. [carboxy-11C]
salicylic acid to acetyl-[carboxy-11C]salicylic acid was performed using
acetylchloride in CH2Cl2 with a radiochemical yield of 65 ± 4 %.
Lubeluzole, a new cerebroprotective compound for use in ischemic stroke, was
labelled via 11C-methylation of the corresponding desmethyl compound. The main
reaction parameters like concentration of precursor, time, temperature, solvent
and added base were investigated. Under optimized conditions a RCY of 82 ± 3 %
was obtained at room temperature within one minute. A labelled side product
was identified as (endo-methyl)-lubeluzole and its formation was suppressed
by the choice of DMSO as the most suitable solvent.
Furthermore, a new method for the radiosynthesis of n.c.a. [11C]ureas was
developed which avoided the use of the highly toxic [11C]COCl2 (phosgene).
Starting from the in target produced n.c.a. [11C]CO2 and subsequent dehydration
of intermediately formed [11C]carbamates, an efficient one-pot synthetic
procedure could be established. The model compound aniline could efficiently
be converted with n.c.a. [11C]CO2 into the corresponding carbamate salt and
subsequently be dehydrated with phosphorylchloride to give [11C]phenylisocyanate.
In contrast to reactions under stoichiometric conditions, the labelled
isocyanate was isolated in relatively low RCY (16 ± 4 %) because it reacted
in situ with the excess of aniline to the corresponding [11C]urea (65 ± 4 % RCY).
Correspondingly, the excess of the dehydrating reagent phosphorylchloride caused
a consecutive reaction, thereby generating N,N´-diphenyl[11C]carbodiimide
as a side product, although in low RCY (< 5 %). Therefore, the isocyanate
and the urea cannot be prevented from further reaction under n.c.a. reaction
conditions. Also, attempts to isolate and analyze the carbamate formed in
the first reaction step failed due to its high reactivity and water sensitivity.
Hence, optimization of the individual reaction parameters of the consecutive
steps was performed by determining the radiochemical yields of the isocyanate,
the urea and the carbodiimide. Optimization of the reaction parameters showed
that the temperature of the carbamate formation was the critical factor for
obtaining a high RCY.
11C-Carbonylation of benzylamine and phenethylamine resulted in 80 - 90 % and
20 - 30 % RCY, respectively. In both cases, no labelled isocyanates were
isolated due to the high nucleophilicity of the amines.
For possible synthesis of several radiopharmaceuticals containing the
benzimidazolone moiety, the 11C-carbonylation was performed with ortho
diaminobenzene as a model compound. The desired cyclized product was obtained
in 20 - 30 % RCY, while a competing reaction yielded the open-chain urea with
about 40 % RCY.
Schirbel, Andreas
Zur Synthese trägerarmer PET-Radiotracer mit Kohlenstoff-11
110 S., 1998
Carbon-11 offers the unique possibility of authentic labelling of molecules as
radioindicators for non invasive and quantitative determination of physiological
functions via positron emission tomography (PET). Therefore, the goal of this thesis
was to synthesize of different n.c.a. 11C-labelled pharmaceuticals for in vivo
distribution studies with PET.
Neuerscheinungen
Schriften des Forschungszentrums Jülich
Ihre Ansprechperson
Heike Lexis
+49 2461 61-5367
zb-publikation@fz-juelich.de