Blood‐Brain Barrier Transport of 1‐Aminocyclohexanecarboxylic Acid, a Nonmetabolizable Amino Acid for In Vivo Studies of Brain Transport

Abstract

Regional transport of 1-aminocyclohexanecarboxylic acid (ACHC), a nonmetabolizable amino acid, across the blood-brain barrier was studied in pentobarbital-anesthetized rats using an in situ brain perfusion technique. The concentration dependence of influx was best described by a model with a saturable and a nonsaturable component. Best-fit values for the kinetic constants of the frontal cortex equaled 9.7 X 10(-4) mumol/s/g for Vmax, 0.054 mumol/ml for Km, and 1.0 X 10(-4) ml/s/g for KD in the absence of competing amino acids. Saturable influx could be reduced by greater than 85% by either L-phenylalanine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, consistent with transport by the cerebrovascular neutral amino acid transport system. The transport Km for ACHC was one-fifth that for the more commonly used homologue, 1-aminocyclopentanecarboxylic acid, and was similar to values for several natural amino acids, such as L-methionine, L-isoleucine, and L-tyrosine. The results indicate that ACHC may be a useful probe for in vivo studies of amino acid transport into brain.

Permeation thresholds for hydrophilic small biomolecules across microvascular and epithelial barriers are predictable on basis of conserved biophysical properties

“…By taking into consideration the observations of this study on the permeation potential of the spectrum of small molecule hydrophiles of neutralized biophysical character, ranging from the pure polyneutral, neutral-cataniononeutral, mixed polyneutral to neutral, it can be surmised that only the subset of these neutralized hydrophiles that are either absolutely or relatively restricted to permeation across inter-endothelial tight junction or inter-epithelial junction pore complexes due to sufficient hydrophilicity for size or due to sufficient molecular size (pure polyneutral, neutral-cataniononeutral, mixed polyneutral), become local substrates for either endothelial or epithelial cell uptake, which is via cell membrane protein channel for local intracellular uptake, and furthermore, for junction pore complex permeable neutralized hydrophiles, the interplay of hydrophilicity per size and absolute molecular size are the determinants of saturable kinetics of the second order, for example, as it applies to the trans-barrier pore permeation kinetics of essential amino acids (Aoyagi et al 1988; Pardridge 1977). …”

Evaluation of unnatural cyclic amino acids as boron delivery agents for treatment of melanomas and gliomas

“…This has been described in detail in a recently published report (Chandra et al, 2013). These types of unnatural amino acids have been shown to cross an intact BBB due to the presence of L-amino acid transporter (Aoyagi et al, 1988), which also is upregulated in high grade gliomas (Detta et al, 2009). Both of these characteristics may enhance the uptake of cis -ABCPC and cis -ABCHC by infiltrating tumor cells in the normal brain.…”

“…These studies revealed that the cyclic amino acids localized in these tumors at higher concentrations than BPA (Hubner et al, 1998; Nichols et al, 2002). The fact that they are water soluble and cross the blood-brain barrier (BBB) (Aoyagi et al, 1988) provided the stimulus to further evaluate them as delivery agents for BNCT. This was especially true because of their ability to target infiltrating tumor cells within normal brain (Chandra et al, 2013; Kabalka et al, 2001, 2004, 2006, 2009).…”

Synthesis of a series of boronated unnatural cyclic amino acids as potential boron neutron capture therapy agents

“…The potential use of boron compounds for the treatment of cancer is based upon the unique nuclear properties of the 10 B nucleus and its high capacity to absorb thermal neutrons. The resulting activated 11 B nucleus, generated by neutron capture, undergoes fission and releases an α-particle and a high-energy lithium-7 ion. The linear energy transfer (LET) of these heavily charged particles has a range of approximately one cell diameter and thus they are lethal to the cells in which they are generated.…”

“…In fact, one of the drugs currently in BNCT clinical trials is an amino acid, 4-dihydroxyborylphenylalanine (BPA). [10] It is also known that 1-aminocycloalkanecarboxylic acids cross the blood-brain barrier [11] and that they are metabolically stable. [12] Positron emission tomographic (PET) investigations [13] using carbon-11 labeled 1-aminocyclobutanecarboxylic acid (ACBC) demonstrated that this amino acid localizes in tumors more avidly than BPA.…”