title: Synthesis of specific SPECT-radiopharmaceutical for tumor imaging based on methionine: 99mTc-DTPA-bis(methionine).
abstract: Methionine-diethylenetriaminepentaaceticacid-methionine [DTPA-bis(Met)] was synthesized by covalently conjugating two molecules of methionine (Met) to DTPA and was labeled with (99m)Tc in high radiochemical purity and specific activity (166-296 MBq/micromol). Kinetic analysis showed K(m) of 12.95 +/- 3.8 nM and a maximal transport rate velocity (V(max)) of 80.35 +/- 0.42 pmol microg protein(-1) min(-1) of (99m)Tc-DTPA-bis(Met) in U-87MG cells. DTPA-bis(Met) had dissociation constants (K(d)) of 0.067 and 0.077 nM in U-87MG and BMG, respectively. (35)S-methionine efflux was trans-stimulated by (99m)Tc-labeled DTPA conjugate demonstrating concentrative transport. The blood kinetic studies showed fast clearance with t(1/2) (F) = 36 +/- 0.5 min and t(1/2) (S) = 5 h 55 min +/- 0.85 min. U-87MG and BMG tumors saturated at approximately 2000 +/- 280 nmol/kg of (99m)Tc-DTPA-bis(Met). Initial rate of transport of (99m)Tc-DTPA-bis(Met) in U-87MG tumor was found to be 4.68 x 10(-4) micromol/kg/min. The tumor (BMG cell line, malignant glioma) grafted in athymic mice were readily identifiable in the gamma images. Semiquantitative analysis from region of interest (ROI) placed over areas counting average counts per pixel with maximum radiotracer uptake on the tumor was found to be 11.05 +/- 3.99 and compared ROI with muscle (0.55 +/- 0.13). The tumor-to-contralateral muscle tissue ratio of (99m)Tc-DTPA-bis(Met) was found to be 23 +/- 3.3. Biodistribution revealed significant tumor uptake and good contrast in the U-87MG, BMG, and EAT tumor-bearing mice. In clinical trials, the sensitivity, specificity, and positive predictive values were found to be 87.8%, 92.8%, and 96.6%, respectively. (99m)Tc-DTPA-bis(Met) showed excellent tumor targeting and has promising utility as a SPECT-radiopharmaceutical for imaging methionine-dependent human tumors and to quantify the ratio of MET(+)/HCY(-).
authors.affiliation: Division Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Road, Delhi-110054, India.
authors.forename: Puja Panwar
authors.initials: PP
authors.lastname: Hazari
authors.forename: Gauri
authors.initials: G
authors.lastname: Shukla
authors.forename: Vijay
authors.initials: V
authors.lastname: Goel
authors.forename: Krishna
authors.initials: K
authors.lastname: Chuttani
authors.forename: Nitin
authors.initials: N
authors.lastname: Kumar
authors.forename: Rajnish
authors.initials: R
authors.lastname: Sharma
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Mishra
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D004355:Drug Stability; D005260:Female; D006801:Humans; D007700:Kinetics; D008715:Methionine / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D011786:Quality Control; D011817:Rabbits; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D002614:Chelating Agents; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C549406:technetium 99m DTPA-bis(methionine); D004369:Pentetic Acid; D008715:Methionine