SYNTHESIS, IN-VITRO VALIDATION AND IN-VIVO PHARMACOKINETICS OF [I-125] PHENYL)ETHYL]-N-METHYL-2-(1-PIPERIDINYL)ETHYLAMINE - A HIGH-AFFINITYLIGAND FOR IMAGING SIGMA-RECEPTOR POSITIVE TUMORS

henyl)ethyl]-N-methyl-2-(1-piperidinyl)ethylamine, IPEMP, and the corr esponding bromo derivative, BrPEMP, have been synthesized and characte rized. Both BrPEMP and IPEMP were evaluated for sigma-1 and sigma-2 su btype receptor affinities and found to possess very high affinities fo r both receptor subtypes. The precursor for radioiodination n-tributyl stannylphenylethylpiperidinylethylamine was prepared from its bromo de rivative by palladium-catalyzed stannylation reaction. Radioiodinated 4-[I-125]PEMP was readily prepared in high yields and high specific ac tivity by oxidative iododestannylation reaction using chloramine-T as oxidizing agent. Sites labeled by 4-[I-125]PEMP in guinea pig brain me mbranes showed high affinity for BD1008, haloperidol, and (+)-pentazoc ine (Ki = 5.06 +/- 0.40, 32.6 +/- 2.75, and 48.1 +/- 8.60 nM, respecti vely), which is consistent with sigma receptor pharmacology. Competiti on binding studies of 4-[I-125]PEMP in melanoma (A375) and MCF-7 breas t cancer cells showed a high affinity, dose-dependent inhibition of bi nding with known sigma ligand -dichlorophenyl)ethyl]-N-methyl-2-(1-pyr rolidinyl) ethylamine, BD1008 (Ki = 5, 11 nM, respectively), supportin g the labeling of sigma sites in these cells. Haloperidol, however sho wed a weaker (Ki = 100-200 nM) affinity for the sites labeled by 4-[I- 125]PEMP in these cells. Biodistribution studies of 4-[I-125]PEMP in r ats showed a fast clearance of this radiopharmaceutical from blood, li ver, lung, and other organs. A co-injection of 4-IPEMP with 4-[I-125]P EMP resulted in 37%, 69%, and 35% decrease in activity in liver, kidne y, and brain (organs possessing sigma receptors), respectively at 1-h postinjection. These results suggest that 4-[I-125]PEMP is a promising radiopharmaceutical for pursuing further studies in animal models wit h tumors.