Optimization of the small-scale synthesis of DOTA-Tyr3-octreotide

MARTIN EDREIRA, LAURA MELENDEZ-ALAFORT AND STEPHEN MATHER

NUCLEAR MEDICINE COMMUNICATIONS

Año: 2002 vol. 23 p. 493 - 499

0143-3636

The clinical potential of 111In and 90Y labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acidconjugated Tyr3-octreotide (DOTA-TOC) have been reported in a number of publications, and Phase IIclinical trials of 90Y-DOTA-TOC are currently in progress. However, to date, only a summary of the largescalepreparation of these radiopharmaceuticals has been published. This publication aims to describe ourexperience of the small-scale synthesis of DOTA-TOC in the hope that this will assist others in thepreparation of this and other similar radioconjugates. DOTA in the form of the tri-t-butyl ester was coupledto the Lys5 (BOC) protected Tyr3-octreotide in N,N-dimethylformamide or N-methyl-2-pyrolidinone, in athree-step reaction involving conjugation, using O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) and diisopropylethyamine (DIPEA) as coupling reagents, deprotection withtrifluoroacetic acid and HPLC purification of the conjugates. The product was obtained in final yields of60+5%. The purified product was characterized by mass spectroscopy, showing a molecular weight of1421.55+0.08. In somatostatin receptor binding assays, the unlabelled DOTA-TOC showed an effectivedisplacement of 99mTc labelled HYNIC-TOC (where HYNIC is hydrazinonicotinamide)(IC50 = 0.31+0.07 nm), confirming the retention of receptor-binding affinity. The conjugate could beefficiently labelled with 111In by addition of 111InCl3 and ammonium acetate buffer pH5 and heating (958C,20 min).