RAD-140 (Testolone) Research Guide

What Is RAD-140?

RAD-140 (Testolone) is a non-steroidal selective androgen receptor modulator (SARM) discovered and developed by Radius Health, Inc. It was first described in a 2010 patent and subsequently published by Miller et al. (2011) in ACS Medicinal Chemistry Letters.

Unlike steroidal androgens (testosterone, nandrolone, DHT), RAD-140 is a synthetic small molecule with no steroidal backbone. It binds the androgen receptor with high affinity — reported binding affinity Ki ~7 nM, comparable to or exceeding testosterone — but activates it with tissue-selective coactivator recruitment that produces different downstream effects in different tissues.

RAD-140 is not approved by any regulatory authority as a therapeutic product. It is supplied as a research chemical for qualified investigators conducting in vitro or animal research. It is prohibited in sport under WADA S1 (Anabolic Agents).

AR Agonism Mechanism

All SARMs, including RAD-140, act through the androgen receptor (AR), a ligand-activated transcription factor belonging to the nuclear receptor superfamily. The selectivity mechanism involves:

• Coactivator-selective activation: When RAD-140 binds AR, the receptor adopts a slightly different conformation than when testosterone binds. This altered conformation recruits different coactivator proteins in different tissues, producing tissue-specific transcriptional outputs.
• No 5α-reductase conversion: Testosterone is converted to the more potent DHT in prostate and skin cells by 5α-reductase. RAD-140's non-steroidal structure cannot be converted — no DHT-like amplification in androgen-sensitive tissues.
• No aromatization: Testosterone converts to estradiol via aromatase. RAD-140 does not aromatize — relevant for research designs studying AR-specific vs. ER-mediated effects.

Tissue Selectivity vs Testosterone

The tissue selectivity of RAD-140 vs testosterone has been quantified in rodent models using the anabolic:androgenic ratio — comparing effects on levator ani muscle (anabolic proxy) vs ventral prostate (androgenic proxy):

Note: Anabolic:androgenic ratios are derived from orchiectomized rodent assays and are not directly predictive of human selectivity.

Muscle & Bone Preclinical Data

The published Miller et al. (2011) paper reported key preclinical findings:

• Lean mass (cynomolgus monkeys): Castrated male cynomolgus monkeys treated with RAD-140 (0.01–0.1 mg/kg/day oral for 28 days) showed dose-dependent lean mass gains comparable to testosterone propionate at 1 mg/kg, with significantly lower prostate stimulation.
• Prostate weight: At equi-anabolic doses, RAD-140 produced <10% the prostate weight increase of testosterone in the monkey model.
• LH/FSH suppression: RAD-140, like all AR agonists, suppresses endogenous LH and FSH via hypothalamic/pituitary feedback — relevant for research designs studying gonadotropin axis suppression.
• Bone density: Rodent studies have demonstrated bone density preservation in gonadectomized models, though this data is less extensively published than the muscle data.

Neuroprotection Research

An unexpected and well-documented area of RAD-140 research is neuroprotection. Several published papers have investigated RAD-140 in CNS models:

• HER2+ cancer neuroprotection (Jayaraman et al., 2014): RAD-140 protected neurons from cell death induced by aplidin (a cytotoxic compound used in HER2+ cancer treatment), via AR-mediated MAPK pathway activation.
• Amyloid-β toxicity (Jayaraman et al., 2019): In primary neurons and in a rodent model, RAD-140 protected against Aβ25-35 peptide toxicity. The mechanism involved AR activation of neuroprotective PI3K/Akt signalling.
• Spatial memory (older male rats): RAD-140 improved performance in Morris water maze in aged rats, suggesting AR-mediated neuroprotective effects on learning and memory.

The neuroprotection data has positioned RAD-140 as a potential research tool for neurodegenerative disease models where AR-mediated effects are hypothesized.

Phase I Clinical Context

RAD-140 completed Phase I clinical trials conducted by Radius Health:

• NCT02207842 (2014–2017): Phase I in postmenopausal women with hormone receptor-positive breast cancer. Primary endpoints: safety, tolerability, PK. The trial enrolled patients but limited efficacy data has been publicly shared.
• Status: Radius Health discontinued clinical development of RAD-140 for oncology. The compound has no approved indication.

The existence of Phase I data provides important pharmacokinetic context: RAD-140 is orally bioavailable with t½ in the range of 16–18 hours in rodents. Human PK data from Phase I has not been fully published.

RAD-140 vs LGD-4033

For muscle wasting research with existing human data, LGD-4033 has the advantage of published Phase II RCT data. For neuroprotection and AR selectivity mechanistic studies, RAD-140 has the more extensive literature.