title: Dysprosium-DOTA-PAMAM dendrimers as macromolecular T2 contrast agents. Preparation and relaxometry.
abstract: OBJECTIVE
  The authors have investigated dysprosium [Dy]-DOTA-PAMAM, generation 5 (G = 5) dendrimers as a possible new class of macromolecular T2 contrast agents. The use of DOTA provides a metal complex with greater stability than can be achieved using DTPA as ligand, an important factor in the design of blood pool agents with long half-lives.
  
  
  METHODS
  Generation 5 ammonia-core PAMAM dendrimers were linked to the bifunctional ligand p-SCN-Bz-DOTA. After determination of the number of conjugated DOTA molecules by 1H nuclear magnetic resonance, Dy3+ was titrated at a 90% molar ratio. For comparison, single ionic chelates of Dy-DTPA and Dy-DOTA also were prepared. Using a variable field relaxometer, T1 and T2 relaxation times were measured at 13 different field strengths from 0.05 to 1.5 T and temperatures of 3, 10, 20 and 37 degrees C.
  
  
  RESULTS
  The synthesis resulted in a preparation with 76 DOTA and 68 Dy3+ ions per dendrimer molecule. The T1 relaxivity values for Dy-DTPA, Dy-DOTA, and the Dy-DOTA-based dendrimer all were independent of field strength, with values between 0.12 and 0.20 mM-1 sec-1. At lower fields (0.05-0.1 T), 1/T2 was identical to 1/T1. At higher fields, however, 1/T2 increased quadratically with field strength, with a strong dependence on temperature. The field-dependent component of 1/T2 was up to three times higher for the Dy-DOTA-based dendrimer compared with the single chelate molecules, with coefficients of 0.37 to 0.03 sec-1/Tesla2 for T = 3 to 37 degrees C.
  
  
  CONCLUSIONS
  The results are interpreted with the "inner sphere" theory of susceptibility effects (Curie spin relaxation). The large temperature dependence suggests that the dominant mechanism of relaxation is the contact interaction effect, with the proton residence time as the primary time constant. This largely unexplored relaxation mechanism has the potential to create a new class of T2-selective contrast agents.
authors.affiliation: Laboratory of Diagnostic Radiology Research, National Institutes of Health, Bethesda, MD 20892, USA. jwmbulte@helix.nih.gov
authors.forename: J W
authors.initials: JW
authors.lastname: Bulte
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: M W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: R A
authors.initials: RA
authors.lastname: Brooks
authors.forename: J
authors.initials: J
authors.lastname: Vymazal
authors.forename: M
authors.initials: M
authors.lastname: Holla
authors.forename: J A
authors.initials: JA
authors.lastname: Frank
mesh_terms: D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry; D004419:Dysprosium; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; C116672:dysprosium-DOTA-PAMAM; D004419:Dysprosium; D004369:Pentetic Acid; C055865:dysprosium DTPA