Preparation of 15-(4-[11C]methylphenyl)pentadecanoic acid (MePPA) as a new tracer for studies in animal models

Objectives 15-(4-[123I]Iodophenyl)pentadecanoic acid ([123I]IPPA) is a well known tracer for assessment of fatty acid metabolism. IPPA labelled with positron-emitting iodine-124 (t1/2 = 4.13 d) is suitable for PET-applications but for in-house production of I-124, solid state target systems are often not available. For IPPA, the alternative could be [11C]-labelled 15-(4-methylphenyl)pentadecanoic acid ([11C]MePPA) due to similar size and lipophilicity of iodine atom and the methyl group. [11C]MePPA can principally be obtained by transition metals catalyzed cross-coupling reactions. An attractive approach is offered by Stille reaction between [11C]CH3I and the corresponding tin precursor.

Methods [11C]MePPA was synthesized via a palladium-mediated Stille reaction of [11C]CH3I with methyl 15-(4-tributylstannylphenyl)pentadecanoate. The reaction conditions were optimized using unsaturated tris(dibenzylideneacetone)dipalladium(0) [Pd2(dpa)3] and tri(o-tolyl)phosphine [P(o-tolyl)3] ligand with respect to reaction temperature, reaction time, solvent and precursor concentration. As it is a new tracer, the compound was also synthesized and characterized as a reference standard for [11C]MePPA.

Results The labelled ester was obtained at 80 °C already after 10 min using DMF as a solvent. The ester intermediate was hydrolyzed by 1 M NaOH ethanol at 80 °C for 3 min to give [11C]MePPA in a radiochemical yield > 55%. The radiochemical purity assured by radio HPLC was > 99%. The overall preparation time including hydrolysis, HPLC purification and formulation was 40 min.

Conclusions [11C]MePPA was prepared via Palladium-mediated Stille reaction within 10 min and deprotection of the C-11 labelled intermediate was > 55% using 1 M NaOH in ethanol at 80 °C for 3 min. The new tracer exhibits the unique advantage of releasing [11C]-methylated benzoic acid as the characteristic metabolite after oxidative degradation the fatty acid and, therefore, MePPA appears to be attractive for applications in animal models