In this work we investigated the (radio)chemical properties of model complexes of the general formula fac-[M(L)(CO)3]+ (M = Re, 99mTc,186Re) where L denotes NODAGA-Pyr [1 = 2,2'-(7-(1-carboxy-4-oxo-4-(pyrrolidin-1-yl)butyl)-1,4,7-triazonane-1,4-diyl)diacetic acid] and NOTA-Pyr [2 = 2,2'-(7-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid], which were derived from conjugation of NODAGA/NOTA with pyrrolidine. Further, as proof-of-principle, we prepared NODAGA-sst2-ANT (3) and NOTA-sst2-ANT (4) peptide bioconjugates and explored their complexation with the fac-[Re/99mTc(CO)3]+ core; sst2-ANT denotes the somatostatin receptor (SSTR) antagonist 4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2. Re-1 to Re-4 were synthesized in moderate yields by reacting [Re(CO)3(H2O)3]+ with 1-4. Re-1/2 were characterized with FT-IR, 1D/2D NMR and HR-MS, whereas Re-3/4 were characterized with LC-MS and HR-MS. Receptor binding affinity of Re-3 was demonstrated in SSTR-expressing cells (AR42J, IC50 = 93 nM). Radiolabeled model complexes 99mTc-1/2 were prepared in high radiochemical yields (RCY 80-100%) by reacting [99mTc/186Re(CO)3(H2O)3]+ with 1/2 and correlated well with the respective Re-1/2 in comparative HPLC studies. The 99mTc-3/4 tracers were prepared (RCY &gt;90%) and identified in a similar manner. For all radiotracers, lipophilicity was determined via the “shake-flask” method (PBS/n-octanol) and logD7.4 values ranged from -1.0 to -3.3. All radiocomplexes were challenged in vitro at physiological conditions (pH 7.4, 37 oC) against 1 mM L-histidine and 1 mM L-cysteine and remained intact through 24 h (or 48 h for 186Re-1/2). Similarly, serum stability studies displayed no decomposition and low non-specific binding of 10-31% through 20 h. Biodistribution of 99mTc-3 in healthy CF-1 mice demonstrated rapid clearance, predominantly via the renal system (% ID in urine: 82 at 1 h, 88 at 4 h), with moderate kidney retention (% ID/g: 11 at 1h, 5 at 4 h) and low non-specific uptake in other organs/tissues, indicating a favorable pharmacokinetic profile. These data establish NOTA and NODAGA as outstanding bifunctional chelators for the fac-[M(CO)3]+ core, with great promise for applications in the design and development of organometallic radiopharmaceuticals. Ongoing biodistribution studies in mice bearing AR42J xenografts will further probe the potential of 99mTc-3/4 as SPECT imaging agents for SSTR-positive neuroendocrine tumors.

NOTA and NODAGA 99mTc/186Re-tricarbonyl complexes: Radiochemistry of model complexes and in vivo evaluation of a 99mTc-NODAGA-SSTR antagonist bioconjugate

255th National Meeting (2018)

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