Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy

Abstract

Lipophilicity is explored in the biodistribution (BD), pharmacokinetics (PK), radiation dosimetry (RD), and toxicity of an internally administered targeted alpha-particle therapy (TAT) under development for the treatment of metastatic melanoma. The TAT conjugate is comprised of the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated to melanocortin receptor 1 specific peptidic ligand (MC1RL) using a linker moiety and chelation of the 225Ac radiometal. A set of conjugates were prepared with a range of lipophilicities (log D 7.4 values) by varying the chemical properties of the linker. Reported are the observations that higher log D 7.4 values are associated with decreased kidney uptake, decreased absorbed radiation dose, and decreased kidney toxicity of the TAT, and the inverse is observed for lower log D 7.4 values. Animals administered TATs with lower lipophilicities exhibited acute nephropathy and death, whereas animals administered the highest activity TATs with higher lipophilicities lived for the duration of the 7 month study and exhibited chronic progressive nephropathy. Changes in TAT lipophilicity were not associated with changes in liver uptake, dose, or toxicity. Significant observations include that lipophilicity correlates with kidney BD, the kidney-to-liver BD ratio, and weight loss and that blood urea nitrogen (BUN) levels correlated with kidney uptake. Furthermore, BUN was identified as having higher sensitivity and specificity of detection of kidney pathology, and the liver enzyme alkaline phosphatase (ALKP) had high sensitivity and specificity for detection of liver damage associated with the TAT. These findings suggest that tuning radiopharmaceutical lipophilicity can effectively modulate the level of kidney uptake to reduce morbidity and improve both safety and efficacy.

H3TPAN-Triazole-Bn-NH2: Tripicolinate Clicked-Bifunctional Chelate for [225Ac]/[111In] Theranostics

“…in the SPECT/CT scans. Transportation and metabolism through splenic lymphocyte and macrophage-mediated pathways have been shown to influence the pharmacokinetics of drug molecules, − wherein the size and lipophilicity of a given drug are strongly correlated with liver and spleen uptake . In the case of [ 111 In]­[In­(TPAN-triazole-Bn-Aoc-Pip-Nle-CycMSH hex )], the lipophilicity (log D 7.4 = −1.53) strongly influences the pharmacokinetic profile, leading to high accumulation in these nontarget organs, and consequently low bioavailability and thus low tumor uptake, as reflected in the time–activity curves of this radiotracer.…”

Preclinical assessment of Alzheimer's disease using novel designed 99mTc‐labeled RGD‐based pro‐apoptotic cyclic peptide as a promising SPECT agent

“…Interestingly, our proposed radiotracers were not observed to retain in kidneys, which may cause nephrotoxicity as other peptide‐based radiotracers do. [ 36,37 ] Furthermore, the biodistribution pattern of 99m Tc‐DTPA (as reference study) using LAT treated Balb/c mice models at various time points indicated no noticeable uptake in brain region as well as upper body organs. The high uptake of 99m Tc‐DTPA was seen in liver and kidneys being a blood flow agent and has no target specificity for other organs (as depicted in Table S3, see ESI).…”

N-(2-Tetrafluoro(trifluoromethyl)-λ6-sulfanyl(CF3SF4)-ethyl) Amines: The Influence of the CF3SF4 Group on Lipophilicity and pKa

“…All reactions were affected in oven-dried glassware under an argon atmosphere. trans-CF 3 SF 4 Cl was prepared after the literature [2]. Dry DCM was freshly distilled from CaH 2 .…”

“…Lipophilicity calculated as log P determines the characteristic of biomolecules, such as absorption, distribution, excretion, and toxicity . Fluorine is the most electronegative atom ( X r = 3.98), with a polarizability (0.14) as determined by Hansch-Leo hydrophobic parameter (π) …”