Dual Isotope Labeled Multimeric PSMA Ligands

Exact quantification of biodistribution and tumor uptake of endoradiotherapeutics is highly desirable for therapy optimization. Currently, therapy planning for radiometallated compounds (e.g., sst2- or PSMA-ligands labeled with Y-90, Lu-177, or Bi-213) often relies on the respective Ga-68 PET tracers, thus lacking precision because pharmacokinetics of the structurally different diagnostics and therapeutics are not identical. Dual-isotope labeled tracers could circumvent this problem by allowing for direct PET-based dosimetry. Methods: Phosphinate chelators with selectivity for Ga-68 (TRAP) and lanthanides (DOTPI) were tethered together and further equipped with 3 copies of DBCO-Ahx-KuE or PA-Ahx-KuE (DBCO = 5-aza-1,3-dibenzocyclooctyne, Ahx = 6-aminohexanoic acid, KuE = Glu-urea-Lys, PA = 4-pentynoic acid), employing Cu(I)-catalyzed (CuAAC) as well as strain-promoted click chemistry (SPAAC). The TRAP chelating site of the resulting constructs DOTPI(PA-Ahx-KuE)3(TRAP) (1) and DOTPI(DBCO-Ahx-KuE)3(TRAP) (2) was selectively saturated with cold Ga(III) by reaction with excess Ga(III) and subsequent by removal of DOTPI-bound Ga(III) with Na2EDTA, followed by manual labeling with Lu-177 and Bi-213. Likewise, the compounds containing cold Lu(III) or Bi(III) in the DOTPI cage, obtained by M(III) complexation and subsequent treatment with Na3DTPA, were labeled with Ga-68 in a standard automated procedure. Lu-177 and Ga-68-labeled compounds were used for biodistribution studies and PET imaging, respectively, in LNCaP-xenografted SCID mice. Results: For DOTPI-TRAP conjugates 1 and 2, the complementary chelation selectivity of DOTPI (lanthanides and large trivalent metal ions) and TRAP (trivalent gallium) enabled site-specific complexation of the respective (radio)metal ions and thus, chemoselective radiolabeling with two independent radionuclides. The nonradioactive compounds, [natBi][natGa]-1, 2, and [natLu][natGa]-2 exhibited comparably high PSMA affinities (IC50 = 2.5 ± 0.2, 1.8 ± 0.4 and 2.8 ± 0.3 nM, respectively). Presence of the DBCO moieties effected a less pronounced hydrophilicity of [natLu][68Ga]-2 (logD = -3.8 ± 0.1) compared to [natBi][68Ga]-1 (-4.4 ± 0.1). Bi-213 labeling of [natGa]-1 required lower concentration than DOTA, pointing at a higher Bi-213 labeling efficiency of DOTPI than DOTA. Comparable PET imaging results were obtained for [natBi][68Ga]-1 and [natLu][68Ga]-2 for which a ROI-based tumor uptake of 3.35 ± 0.17 %ID/g (60 min p.i., n =4) was found. Conclusions: DOTPI-TRAP conjugates allow for preparation of theranostic pairs consisting of a Ga-68-PET tracer and a radiometallated therapeutic with indentical chemical structure. Their co-injection enables exact PET-based dosimetry, which is particularly attractive for combinations of Ga-68- and Bi-213-labeled compounds due to comparable nuclide half lives (68 and 43 min, respectively) and the lack of other imaging possibilities for Bi-213.

WURZER A;  SEIDL C.;  MORGENSTERN Alfred;  BRUCHERTSEIFER Frank;  WESTER Hans-Jürgen;  NOTNI Johannes; 

2016-12-01

SPRINGER

JRC103083

1619-7070,